BACKGROUND The majority of recent, well-designed studies have shown that long-term cigarette smoking increases colorectal cancer risk, but older studies with shorter durations of exposure often found no association. This study aimed to examine colorectal cancer risk by smoking exposure using data collected in the late-1950s and early-1960s. METHODS This case-control study examined colorectal cancer risk by lifetime smoking history. There were 1365 patients who visited Roswell Park Cancer Institute (RPCI) between 1957 and 1965 diagnosed with primary, incident colorectal cancers that were matched to 4096 malignancy-free controls on gender and age. Odds ratios were calculated using separate logistic regression models for each smoking exposure, while controlling for other tobacco use, county of residence, race, age, gender, and body mass index (BMI). RESULTS The adjusted OR for individuals who reported their greatest level of smoking to be more than 1 pack/day was 0.87 (95% CI=0.67-1.15). Among those who smoked 42 or more years, the adjusted OR was 0.89 (95% CI=0.68-1.15) compared to those who never smoked. For individuals who smoked more than 45 pack-years, the OR was 0.92 (95% CI=0.72-1.19). The results did not differ significantly by gender, although men had considerably greater exposure compared to women. Results also did not differ by colorectal sub-site. CONCLUSION No association was found between long-term cigarette smoking and colorectal cancer risk. These results are in accord with studies that followed cohorts throughout the 1950s and 1960s. Methodological limitations, such as missing data on covariates and the higher incidence of smoking-related illness in a hospital setting, may have contributed to the null results found in this study. Prolonged population exposure to cigarettes and perhaps a changing product may explain why more recent studies have reported a positive association between smoking and colorectal cancer.