Microsatellite instability (MSI) occurs in 10-20% of the sporadic colon carcinomas and appears to be primarily due to alterations in hMLH1 and hMSH2. Little is known about the role of diet in MSI-related colon carcinogenesis. We used data from a Dutch population-based case-control study on sporadic colon carcinomas (184 cases and 259 controls) to evaluate associations between dietary factors previously reported as being associated with colon cancer risk and MSI, hMLH1 expression, and hMLH1 hypermethylation. Red meat intake was significantly differently related to microsatellite instability-high (MSI-H) tumors compared with microsatellite instability-low/microsatellite stable (MSI-L/MSS) [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.9]. It was inversely associated with MSI-H tumors when compared with the population-based controls (OR, 0.5; 95% CI, 0.2-1.2) and positively associated with MSI-L/MSS tumors (OR, 1.5; 95% CI, 0.9-2.6). A positive association was observed for alcohol intake with MSI-H tumors (OR, 1.9; 95% CI, 0.8-4.7). Fruit consumption seemed to especially decrease the risk of MSI-H tumors with hypermethylated hMLH1 (Methyl(+) tumors) [Methyl(+) versus controls: OR = 0.4 and 95% CI = 0.2-0.9; MSI-H tumors without hypermethylated hMLH1 (Methyl(-) tumors) versus controls, OR = 1.2 and 95% CI = 0.8-1.7; Methyl(+) versus Methyl(-) tumors, OR = 0.2 and 95% CI = 0.1-0.9]. Most other evaluated dietary factors were not distinctively associated with a specific MSI or hMLH1 methylation status. Our data suggest that red meat consumption may enhance the development of MSI-L/MSS carcinomas in particular, whereas alcohol intake appears to increase the risk of MSI-H tumors. Fruit consumption may especially decrease the risk of MSI-H carcinomas exhibiting epigenetically silenced hMLH1.