Of 114 recipients of pancreatic, renal, and bone marrow transplants who were given trimethoprim-sulfamethoxazole (TMP-SMZ) for antimicrobial prophylaxis, 44 (39%) had a total of 52 fecal isolates of TMP-SMZ-resistant gram-negative bacilli. In most of these 44 patients, the resistant isolate was found at a concentration of ≥106 organisms/ml of feces. Escherichia coli was the most frequent of the isolates, and Citrobacter freundii was the next most frequent. Eight of the 114 transplant recipients had gram-negative bacteremia; in six of these eight patients, a TMP-SMZ-resistant gram-negative bacillus was the etiologic agent of bacteremia. Four of the latter six patients had stool cultures analyzed prior to the detection of bacteremia; all four had high concentrations (≥108/ml) of fecal TMP-SMZ-resistant E. coli one to 20 days before they were found to have E. coli bacteremia. In each of these instances, the E. coli isolates from the stool and the blood had similar antibiograms. These findings indicated that resistance to TMP-SMZ is becoming more prevalent and that the screening of patients for the presence of fecal TMP-SMZ-resistant Enterobacteriaceae prior to initiation of long-term therapy with this antimicrobial agent may be worthwhile.