Despite the possible benefit from avoiding stone surgery with all its possible complications, oral chemolysis is rarely performed in patients with urinary stones suspected of uric acid content. Among the reasons for its limited use is the sparse and low-quality data on its efficacy and the lack of reliable factors predicting its outcome. We thus performed a retrospective single-center cohort study of 216 patients (median patient age 63 years) with 272 renal (48%) and/or ureteral (52%) stones treated with oral chemolysis from 01/2010 to 12/2019. Patients with low urine pH (< 6), low stone density upon non-contrast enhanced computed tomography (NCCT), radiolucent urinary stones on plain radiography, and/or a history of uric acid urolithiasis were included. Potassium citrate and/or sodium/magnesium bicarbonate were used for alkalization (target urine pH 6.5-7.2). Median stone size was 9 mm, median stone density 430 Hounsfield Units. Patients with ureteral stones < 6 mm were excluded since stones this small are very likely to pass spontaneously. The stone-free status of each patient was evaluated after 3 months using NCCT. Oral chemolysis was effective with a complete and partial response rate of stones at 3 months of 61% and 14%, respectively; 25% of stones could not be dissolved. Lower stone density (OR = 0.997 [CI 0.994-0.999]; p = 0.008) and smaller stone size (OR = 0.959 [CI 0.924-0.995]; p = 0.025) significantly increased the success rate of oral chemolysis in multivariate logistic regression analysis. More precise stone diagnostics to exclude non-uric-acid stones could further improve outcome.