Background: Influenza vaccination may be less immunogenic in transplant recipients than in healthy people. Influenza A (H1N1) and B circulating viruses during the 2007-2008 epidemic were different from those contained in that season’s vaccine. In that epidemic, influenza vaccine effectiveness against culture-confirmed influenza was 44%. Objective: To describe clinical, immunological, and virological characteristics of 18 transplant recipients who developed influenza during the 2007-08 epidemic despite influenza vaccination (tx-vac-flu), and compare them to 6 transplant recipients who developed influenza in the absence of influenza vaccination (tx-no vac-flu), 12 previously healthy people who developed influenza (healthy-flu), and 13 transplant recipients who received influenza vaccination and did not develop influenza (tx-vac-no flu). Methods: Case ascertainment was through microbiology and electronic medical records. A case of influenza was defined by a clinical presentation of an influenza-like illness, plus a positive influenza A or B multiplex real time polymerase chain reaction (Prodesse, Inc. Waukesha, WI) on a nasopharyngeal swab. Results: Of the 36 patients with influenza, 22 had influenza A, and 15 had influenza B (1 transplant recipient had both serotypes simultaneously). Types of transplant were lung (11), hematopoietic stem cell (8), heart (7), liver (3), kidney (3), kidney + pancreas (3), liver + kidney (1), and liver + pancreas (1). Patients in the tx-vac-flu group were significantly older than patients in the tx-no vac-flu group [median 61 vs. 50.5 year, (P=0.02), the healthy-flu group [median 49.5 years (P=0.04)], and the tx-vac-no flu group [median 53 years (P=0.02)]. Influenza occurred 1,410 (261-3,467) days {median [interquartile (IQR) range]} after transplant in the tx-vac-flu group, compared to 175 (40-1,064] days in the tx-no vac-flu group (P=0.18). Influenza occurred 114 days (median [IQR 99-137]) after vaccination in the tx-vac-flu group. Immunoglobulin G levels and immune function assay levels were not significantly different between the 3 transplant groups. There were no statistically significant differences in the incidence of fever, headache, cough, rhinorrhea, sore throat, malaise, shortness of breath, exposure to contacts with similar symptoms, presence of infiltrates on chest roentgenograms, or the estimated influenza viral loads among the 3 groups who had influenza. Patients in the tx-vac-flu group were treated with oseltamivir significantly more frequently than the healthy-flu group [94% vs. 50% (P=0.0006)], but not the tx-no vac-flu group [100% (P=0.7)]. Duration of treatment with oseltamivir was not significantly different among the 3 groups who had influenza. Patients in the tx-vac-flu group had concomitant infections significantly more frequently than the healthy-flu group [44% vs. 8% (P=0.043)], but not the tx-no vac-flu group. Patients in the tx-vac-flu group developed pneumonia, and were hospitalized for management of influenza significantly more frequently than patients in the healthy-flu group (P=0.031 and P=0.00007; respectively). Only one patient (6%) in the tx-vac-flu group and none in the tx-no vac-flu or healthy-flu groups required admission to an intensive care unit and mechanical ventilation following influenza. No patients died as a result of influenza. Conclusions: Influenza vaccination did not alter clinical presentation of influenza in transplant recipients, but these patients were hospitalized and developed pneumonia more frequently than healthy people. Transplant recipients who developed influenza despite influenza vaccination were not more immunosuppressed than transplant recipients who were vaccinated and did not develop influenza. Transplant recipients who developed influenza despite influenza vaccination were more likely to have concomitant infections than healthy people with influenza.