The Biojector B2000 gas-powered needle-free injection system (Bioject Inc., Tualatin, Oregon, USA) is undergoing evaluation for the subcutaneous administration of enfuvirtide (Fuzeon; Roche, Hoffaman-LaRoche, Basel, Switzerland) in HIV-infected, treatment-experienced patients [1]. An unexpected complication has been observed in three male patients receiving standard doses of enfuvirtide twice a day by subcutaneous injection with the Biojector. Patient 1 started enfuvirtide on 3 December 2004, but experienced significant problems with nodules and needle phobia. On 10 December 2004, he was instructed in the use of the Biojector and started using it for enfuvirtide administration. His initial experience using the device was good, with only mild injection-site reactions (tenderness and swelling). However, on 10 May 2005, he felt an immediate sensation of ‘electric shock’ in the right upper lateral thigh after administering enfuvirtide in his right buttock, followed by numbness in the same area of the thigh, which persisted for 3 months then resolved without sequelae. After being instructed to avoid joint regions for injection, he has continued to inject enfuvirtide using the Biojector for a total of 8 months without further symptoms. Patient 2 began enfuvirtide in May 2004 but had significant local symptoms of swelling, soreness, and persistent nodules, resulting in limited areas available for injection. On 18 January 2005, he was instructed in the use of the Biojector and started using it for his regular enfuvirtide injections. He experienced a decrease in the number and severity of injection-site reactions thereafter. On 16 April 2005, he injected enfuvirtide using the Biojector to his medial left upper arm just above the elbow. He had an immediate ‘electric shock’ sensation in the forearm, followed by pain and numbness in the region of the left elbow, including the proximal forearm. The pain resolved in 3 weeks and the numbness after 3 months, both without sequelae. After being instructed to avoid injecting in areas near joints, he has continued to use the Biojector for a total of 7 months without further problems. Patient 3 started enfuvirtide in April 2004. After experiencing ongoing problems with injection-site reactions, on 10 January 2005, he was trained in the use of the Biojector and started using it for enfuvirtide administration. Initially, he experienced mild pain, slight redness, and occasional itching after the injections. On 17 February 2005, he injected enfuvirtide using the Biojector at the top of his left anterior thigh just below the inguinal region. He experienced immediate and severe pain from the injection site down to the top of the left knee. Minutes later, he had a feeling of numbness and altered sensation in the same area. He also found the leg painful to move, making walking difficult. The pain resolved after several days, whereas the numbness and dysesthesia persisted, gradually resolving over the next 6 months. He immediately resumed using standard needles and syringes to administer enfuvirtide and elected not to use the Biojector again. A number of factors may have contributed to the symptoms described after enfuvirtide injection using the Biojector (Table 1). First, all of these men had advanced HIV disease and several years of antiretroviral experience, resulting in significant subcutaneous fat wasting and a low body mass index. This may be exacerbated by injections given close to joints, resulting in the nerves in these areas being particularly close to the surface. Of note is the fact that the injection sites the patients used in these cases were not those recommended by the manufacturer of the device. Recommended subcutaneous injection sites for the Biojector are the same as those for standard needles and syringes: the lateral and posterior aspects of the upper arm, the lateral and anterior aspects of the thigh, the upper back, and abdomen [2].Table 1: Characteristics of patients at the time of the event.The occurrence of immediate pain along a nerve distribution, and numbness and other local neurological symptoms after an injection has not previously been described with the use of needle-free injection systems such as the Biojector. In the cases we have seen thus far, the symptoms have been temporary, resolving over 3–6 months. Patients with advanced HIV disease and generalized fat wasting, who are also those most likely to receive enfuvirtide as part of their antiretroviral regimen, may be at the greatest risk of this complication. Fortunately, this seems to be a relatively uncommon occurrence: we observed three episodes in a 6-month period during which more than 20 patients from our clinic were using the Biojector for twice daily enfuvirtide administration, i.e. three events in approximately 7200 Biojector injections for an approximate incidence of 1: 2400. This complication may be avoided if patients are instructed to inject with the Biojector in the recommended areas, away from joints and other areas where nerves are relatively superficial.