Ranitidine has been shown to contain the carcinogen N-nitrosodimethylamine and increase urinary N-nitrosodimethylamine in humans. We investigated whether ranitidine use is associated with increased bladder cancer risk. A nested case-control study was conducted within the Primary Care Clinical Informatics Unit Research database which contains general practice records from Scotland. Bladder cancer cases, diagnosed between 1999 and 2011, were identified and matched with up to 5 controls (based on age, sex, general practice, and date of registration). Ranitidine, other histamine-2 receptor agonists, and proton pump inhibitors were identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression after adjusting for comorbidities and smoking. There were 3,260 cases and 14,037 controls. There was evidence of an increased risk of bladder cancer in ranitidine users, compared with nonusers (fully adjusted OR = 1.22; 95% CI 1.06-1.40), which was more marked with use for over 3 years of ranitidine (fully adjusted OR = 1.43; 95% CI 1.05-1.94). By contrast, there was little evidence of any association between proton pump inhibitor use and bladder cancer risk based on any use (fully adjusted OR = 0.98; 95% CI 0.88-1.11) or over 3 years of use (fully adjusted OR = 0.98; 95% CI 0.80-1.20). In this large population-based study, the use of ranitidine particularly long-term use was associated with an increased risk of bladder cancer. Further studies are necessary to attempt to replicate this finding in other settings.