Background: Regular use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) for a longer period has been inversely associated with colorectal cancer (CRC) risk. However, CRC is a heterogenic disease, and little is known regarding the associations with molecular pathological subtypes. Methods: Analyses included 2444 cases with a first diagnosis of CRC and 3130 healthy controls from a German populationbased case control study. Tumor tissue samples were analyzed for major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype, B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. Information on past and current use of NSAIDs, including aspirin, was obtained by standardized interviews. Multinomial logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: Regular use of NSAIDs was associated with a reduced CRC risk if tumors were MSS (OR=0.66, 95% CI = 0.57 to 0.77), BRAF wildtype (OR=0.67, 95% CI = 0.58 to 0.78), or KRAS wildtype (OR=0.68, 95% CI = 0.58 to 0.80). Regular NSAID use was less clearly and mostly not statistically significantly associated with CRC risk reduction for MSI-high, BRAF-mutated, or KRAS-mutated CRC. In more specific analyses on MSI-high CRC, regular use of NSAIDs was associated with much stronger risk reduction in the absence of BRAF or KRAS mutations (OR=0.34, 95% CI = 0.18 to 0.65) but not with KRAS-or BRAFmutated MSI-high CRC (Pheterogeneity<.001). Results for just aspirin use were similar. Conclusion: Our study suggests variation in risk reduction of CRC subtypes following regular use of NSAIDs and aspirin. Regular use of NSAIDs and aspirin may be more strongly associated with risk reduction of MSI-high CRC without KRAS or BRAF mutation.