Background: Carbapenems are the drug of choice for treatment of infections due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. Current evidence regarding piperacillin-tazobactam (PTZ) as an effective treatment alternative remains controversial. The purpose of this study was to determine the efficacy of PTZ versus carbapenems for treatment of nonbacteremic urinary tract infections (UTIs) due to ESBL-producing Enterobacteriaceae. Methods: A retrospective cohort study of patients treated for ESBL-related UTIs was conducted at three medical centers in the greater Middle Tennessee area. Patients were included if they were ≥ 18 years old, had a positive urine culture with an ESBL-producing organism, and received ≥ 48 hours of treatment with PTZ or carbapenem. Patients with bacteremia as well as those with isolates resistant to the treatment regimen selected were excluded. The primary objective was to determine the difference in clinical response between PTZ and carbapenem for treatment of ESBL-related UTIs. Clinical response was defined as absence of all of the following: (1) repeat admission for UTI caused by the same organism within 6 months, (2) repeat urine culture within 6 months showing growth of the same organism, or (3) a change in antimicrobial regimen due to subjective failure as determined by the ordering provider. Results: A total of 180 patients were included in the analysis (PTZ = 39; carbapenem = 141). There was no difference in clinical response between patients receiving PTZ and carbapenem (74.4% versus 80.9%; P = .38). Conclusion: PTZ may be an effective alternative to carbapenems for treatment of nonbacteremic UTIs due to ESBL-producing Enterobacteriaceae.