Metformin use has been associated previously with a decreased risk of cancer, but its association with renal cell carcinoma has not yet been investigated in observational studies. We aimed to explore the association between the use of metformin and other antidiabetic drugs and the risk of renal cell carcinoma (RCC). We carried out a case–control analysis in the UK-based Clinical Practice Research Datalink. We included individuals with an incident RCC between January 1995 and December 2013 younger than the age of 90 years. Six controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the Clinical Practice Research Datalink before the index date. We included BMI, smoking, alcohol consumption, hypertension, and diabetes mellitus as potential confounders in a multivariate model using conditional logistic regression to calculate odds ratios with 95% confidence intervals, and we carried out a sensitivity analysis restricted only to diabetic cases and controls. Long-term use of metformin was not associated with an altered relative risk of RCC (≥30 prescriptions, adjusted odds ratio 1.18, 95% confidence interval 0.88–1.58), nor was use of other antidiabetic drugs. Results in the sensitivity analysis including only diabetic cases and controls were largely the same. Use of metformin or other antidiabetic drugs was not associated with a materially altered risk of RCC. Further studies are warranted.