Imipenem is considered to confer greater risk for the acquisition of Stenotrophomonas maltophilia than are other beta-lactam antibiotics. We conducted a historical cohort study to directly compare the risks of S. maltophilia acquisition in patients treated with imipenem vs. ceftazidime during a 2-year period; 843 hospitalizations of 759 patients treated with ceftazidime (465 hospitalizations), imipenem (294), or both agents (84) were included. Acquisition, as measured by clinical detection, occurred in 24 hospitalizations. Rates of acquisition did not significantly differ between the imipenem and ceftazidime groups (3.7 vs. 7.1 cases per 10,000 patients days; P = .2). In contrast, patients treated with both agents had higher acquisition rates (19 cases per 10,000 patient days; P = .002). Thus, patients treated with imipenem are not at significantly higher risk for S. maltophilia acquisition than those treated with ceftazidime. The excessive risk for patients treated with both agents may be related in part to longer antibiotic therapy and a longer hospital stay.