Trans-fatty acids have been hypothesized to be carcinogenic, although there are limited data in humans testing this hypothesis. In this study, we examine the association between trans-fatty acids and colon cancer using data from a case (n = 1,993)-control (n = 2,410) study conducted in Utah, Northern California, and Minnesota. Dietary data were collected using a detailed diet history questionnaire, and nutrient values were generated from the Nutrition Coordinating Center nutrient database. After adjustment for other variables, including age at diagnosis, body size, physical activity, aspirin and/or nonsteroidal anti-inflammatory drug (referred to collectively as NSAIDs) use, energy intake, and dietary fiber and calcium, we found a weak association in women [odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-2.0] but not in men (OR = 1.2, 95% CI = 0.9-1.7); no increased risk was observed for the cis form of the fatty acids. For men and women, slightly stronger associations were observed in those > or = 67 years of age (OR = 1.4, 95% CI = 0.9-2.1 for men; OR = 1.6, 95% CI = 1.0-2.4 for women). Those who did not use NSAIDs were at a 50% greater risk of developing colon cancer when they consumed high levels of trans-fatty acids. Women who were estrogen negative, i.e., postmenopausal not taking hormone replace therapy, had a twofold increase in risk from high levels of trans-fatty acids in the diet, while women who were estrogen positive did not experience an increased risk of colon cancer, regardless of level of trans-fatty acids consumed. We believe that these data have important public health implications. It seems prudent to avoid consuming partially hydrogenated fats, since no increased risk was observed for the cis form of fatty acids, while suggestions of increased risk from trans-fatty acids exist for subsets of the population.