The associations between calcium, fat, and cholesterol intake and risk of colorectal cancer were studied in a case-control study conducted in Uruguay. A total of 282 incident and histologically proven cases of adenocarcinomas of the colon and rectum comprised the case series. Five hundred sixty-four hospitalized controls were selected from the same hospitals from which the cases were drawn. Calcium intake was associated with a significant decrease in the risk of colorectal cancer (odds ratio = 0.41, 95% confidence limit = 0.24-0.69 for the uppermost quartile of intake). The associations were similar for colon and rectal cancer. On the other hand, protein and total fat were associated with significantly increased risk of colorectal cancer. A strong interaction between calcium and fat (and cholesterol) intake was found. According to this interaction, calcium effect was maximal at low levels of dietary fat (and cholesterol intake), whereas fat (and cholesterol intake) showed a positive monotonic increase in risk of colorectal cancer at high levels of calcium intake. This finding should be further investigated in other epidemiologic and experimental studies.