In the acute postoperative period, fluid collections are common in lower extremity amputations. Whether these fluid collections increase the risk of infection is unknown. The purposes of this study were to determine (1) the percentage of patients who develop postoperative fluid collections in posttraumatic amputations and the natural course of the collection; (2) whether patients who develop these collections are at increased risk for infection; and to ask (3) are there objective clinical or radiologic signs that are associated with likelihood of infection when a fluid collection is present? We performed a review of all 300 patients injured in combat operations who sustained at least one major lower extremity amputation (at or proximal to the tibiotalar joint) and were treated definitively at our institution between March 2005 and April 2009. We segregated the groups based on whether cross-sectional imaging was performed less than 3 months (early group) after closure, greater than 3 months (late group) after closure, or not at all (control group, baseline frequency of infection). Our primary study cohort where those patients with a fluid collection in the first three months. The clinical course was reviewed and the primary outcome was a return to the operating room for irrigation and débridement with positive cultures. For those patients with cross-sectional imaging, we also collected objective clinical parameters within 24 hours of the scan (white blood cell count, maximum temperature, presence of bacteremia, tachycardia, oxygen desaturation), extremity examination (presence of erythema, warmth, and/or drainage), and characteristics of the fluid collections seen (size of the fluid collection, enhancement, complexity (simple versus loculated), surrounding edema, skin changes, tract formation, presence of air, and changes within the bone itself). The presence of a fluid collection on imaging was analyzed to determine whether it was associated with infection. We further analyzed clinical parameters, objective physical examination findings at the extremity, and characteristics of the fluid collection to determine if there were other parameters associated with infection. Over half (55%) of the limbs demonstrated fluid collection in the early postoperative period and the prevalence decreased in the late group (11%; p = 0.001). There was no association between the presence of a fluid collection and infection. However, there was an association between objective clinical signs at the extremity (erythema and/or drainage) and infection (p < 0.001) in our primary study cohort. Fluid collections are common in combat-related amputations in the immediate postoperative period and become smaller and less frequent over time. In the absence of extremity erythema and wound drainage, imaging of a residual limb to evaluate for the presence of a fluid collection appears to be of little clinical use.