The purpose of this study was to assess the incidence and clinical significance of famotidine-associated thrombocytopenia in the trauma patient population. A retrospective cohort study was performed between January 2003 and May 2009 comparing the consecutive platelet counts of trauma patients treated with intravenous famotidine with a similar group of trauma patients who were not. Patients were excluded if: 1) daily platelets counts for 48 hours were not drawn; 2) if platelet counts were less than 150 × 103/μL on admission or before initiation of famotidine treatment; 3) if patients received heparin or enoxaparin before or during the study period; and 4) if patients were taking famotidine before admission. Platelet counts were then recorded for the day of admission, the day famotidine was started if not on admission, and 24 hours and 48 hours during treatment. Seventy-two of 181 (39.8%) patients treated with famotidine developed thrombocytopenia compared with 23 of 126 (18.3%) untreated patients (P < 0.001). Patients who developed thrombocytopenia were also more likely to have a longer length of stay and higher Injury Severity Scores. Intravenous famotidine therapy was the only variable found to be statistically significant after both univariate and multivariate analysis (P < 0.001 and P = 0.003, respectively). Thrombocytopenia became clinically significant in eight of 181 (4.4%) famotidine-treated patients or 11.1 per cent of those who developed thrombocytopenia. Given these findings, we recommend the use of alternative medications for peptic ulcer prophylaxis in the critically ill trauma patient, especially those who are coagulopathic.