Inconsistent observations in epidemiologic studies on the association between total fat intake and colorectal cancer may be ascribed to opposing effects of individual fatty acids and the presence of other dietary constituents that modify luminal or systemic lipid exposure. We analyzed the data from a population-based case-control study that included 1,163 cases and 1,501 controls to examine the effects of individual fatty acid groups on colorectal cancer risk as well as their interactions with calcium and fiber intake. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression model according to quartile levels of energy-adjusted fatty acid intake. In the bivariable analyses, the risk of colorectal cancer increased with trans fatty acid (TFA) intake (OR for top vs. bottom quartile =1.46, 95% CI 1.17-1.59, p-value for a trend <0.001), but the associations was substantially attenuated in multivariable analyses (p value for a trend = 0.176). However, a significant linear trend in the multivariable OR (p = 0.029) for TFA was present for subjects with lower calcium intake. Furthermore, multivariable ORs progressively decreased with increasing both omega-3 and omega-6 poly- unsaturated fatty acid intake (p-values for linear trend: 0.033 and 0.011, respectively) for subjects with lower dietary fiber intake. These interactions were also significant or marginally significant (p = 0.085 for TFA, 0.029 for omega-3 and 0.068 for omega-6). Our results suggest that populations with lower intake of luminal modifiers, i.e., calcium and fiber, may have differential risks of colorectal cancer associated with dietary fatty acid intake.