Objectives To examine the association between the use of oral antibiotics and subsequent colorectal cancer risk. Design Matched case–control study. Setting General practice centres participating in the Integrated Computerised Network database in Flanders, Belgium. Participants In total, 1705 cases of colorectal cancer diagnosed between 01 January 2010 and 31 December 2015 were matched to 6749 controls by age, sex, comorbidity and general practice centre. Primary outcome measure The association between the number of prescriptions for oral antibiotics and the incidence of colorectal cancer over a period of 1–10 years, estimated by a conditional logistic regression model. Results A significantly increased risk of colorectal cancer (OR 1.25, 95% CI 1.10 to 1.44) was found in subjects with one or more prescriptions compared with those with none after correction for diabetes mellitus. No dose-response relationship was found. Conclusions This study resulted in a modestly higher risk of having colorectal cancer diagnosed after antibiotic exposure. The main limitation was missing data on known risk factors, in particular smoking behaviour. This study did not allow us to examine the causality of the relationship, indicating the need of further investigation.