The effect of betel quid chewing on colorectal cancer (CRC) risk has not been reported. In addition, there is no consensus about the causal relationship between smoking or alcohol consumption and CRC risk. This study investigated the impact of betel quid chewing, cigarette smoking or alcohol consumption on CRC risk in Taiwan. Methods: Two hundred and fifty-eight patients with pathologically proven CRC (153 men, 105 women; mean age, 63.1 years) were recruited from two hospitals in southern Taiwan. The controls were 533 ageand gender-matched cancer-free subjects from the same hospitals. All subjects were interviewed using a standardized questionnaire to collect demographic and substance use data. Results: After adjusting for potential confounding factors, smoking (adjusted odds ratio [aOR], 1.65; 95% CI, 1.1–2.3), but not betel quid chewing (aOR, 1.3; 95% CI, 0.7–2.4) or alcohol drinking (aOR, 1.1; 95% CI, 0.7–1.8), was an independent significant risk factor for developing CRC. The significant risk effect of smoking was seen mainly among men, because the frequency of smokers was much higher among Taiwanese men than women. Conclusion: Our results indicated that consumption of cigarettes but not betel quid or alcohol was a risk factor for male CRC. A large study is necessary to investigate the risk factors for female CRC in Taiwan, and to understand the effect of betel quid exposure on male CRC.