Abstract Background Antibiotic treatment for complicated urinary tract infections (cUTI)/acute pyelonephritis (AP) is often followed by recurrent bacteriuria in the absence of clinical symptoms. To understand factors predictive of clinical and microbiologic outcomes in patients with cUTI/AP, multivariable analyses were undertaken using pooled data from a global, phase 3 cUTI study. Methods Using data from 366 tebipenem pivoxil hydrobromide- and 378 ertapenem-treated patients from the ADAPT-PO study infected with Enterobacterales uropathogens, multivariable analyses for dichotomous efficacy endpoints were performed using logistic regression, and pharmacokinetic-pharmacodynamic (PK-PD) relationships were evaluated. Results Urinary tract anatomical disorders and functional urinary tract or metabolic disorders were predictive of non-response across all efficacy endpoints assessed at test-of-cure (TOC) and late follow-up (LFU) visits, with greater impact on overall and microbiologic than clinical non-response. Independent variables predictive of increased probabilities of successful response for overall response at TOC and microbiologic response at TOC or LFU were baseline creatinine clearance > 50 mL/min and baseline pathogen fluoroquinolone susceptibility. Infection with a phenotypic extended-spectrum beta-lactamase (ESBL)-positive Enterobacterales pathogen was predictive of reduced probabilities of success for microbiologic response at LFU and clinical response at TOC. Meaningful relationships between efficacy endpoints and plasma PK-PD indices were not identified. Conclusions Reductions of overall and microbiologic response in patients with cUTI/AP are associated with anatomical or functional genitourinary disorders, but not with the magnitude or duration of plasma antibiotic exposure. Results of these analyses serve to advance our understanding of factors predictive of outcome in patients with cUTI/AP.