Background: Although Japanese guidelines recommend fluoroquinolones (FQs) and cephalosporins for AUC (acute uncomplicated cystitis) treatment, the emergence of FQ-resistant uropathogens and inappropriate use of antibiotics may lead to treatment failure (TF), and increased healthcare costs. There is a need to understand the epidemiology, treatment patterns, and healthcare cost implications associated with AUC in Japan. Methods: This retrospective cohort study used the Japanese Medical Database Centre database (1 October 2015–30 November 2021). Female patients (≥18 years) had an AUC diagnosis in the same month as ≥1 oral antibiotic prescription claim in the outpatient setting. The population was stratified into cohorts by TF status and history of AUC recurrence prior to index (pre-index recurrence). Baseline demographics were evaluated in the 12-month pre-index period and age standardized prevalence of AUC was calculated. Treatment patterns and AUC-related costs [2022 Japanese Yen (¥)], were reported for the post-index follow-up period. Results: Of 71 476 total patients, 62.46% were aged <50 years. Patients had evidence of TF (n = 3742; 5.24%) and pre-index recurrence (n = 3206; 4.49%). The age standardized prevalence of AUC (2016–2021) decreased from 8.62% to 6.02%, with up to 3.9 million women affected each year. A high proportion of patients with TF received FQs (45.48%) and third generation cephalosporins (43.37%). The mean total AUC-related costs were ¥14 905 and pharmacy costs were ¥1059 per patient, per index AUC episode. Conclusion: Healthcare providers should consider the cost implications for patients with antibiotic TF or a history of AUC recurrence when selecting antibiotics for empiric treatment in Japan.