Introduction: Colorectal cancer (CRC) affects 150,000 Americans each year and is a major cause of mortality and morbidity. Gender and aging are important factors influencing the relative risk and colonic distribution of CRC. In this study, we updated the effect of gender and aging on changing incidence patterns of CRC in the U.S. during the most recent 29 years period for which Surveillance, Epidemiology, and End Results (SEER) database was available. Methods: Using the SEER program of the National Cancer Institute, we identified primary CRC diagnosed between 1973 and 2001. We evaluated temporal changes and analyzed incidence rates per 100,000 person-years based on site, sex and age using the SEER* Stat 5.2 program. Proximal colon was defined as proximal to and including the splenic flexure and distal colon was defined as distal to the splenic flexure including rectum. Results: 1) A total of 366,210 cases of CRC were diagnosed from 1973 to 2001. 2) The CRC incidence increased in both males and females between 1973-1985, and then decreased between 1985-2001. 3) Throughout the 29-year study period, males consistently had about a 35% higher incidence of CRC than the females. 4) When CRC incidence was sub-divided by specific colonic subsites, males had a higher incidence of CRC in all colonic subsites. 5) However, for the entire study period, females had significantly higher proportion of proximal CRC than the males (44% vs. 36%, P<0.01). 6) Between 1973-2001, the proportion of proximal CRC steadily increased in both sexes. Thus, in 1973, 39% of CRC in females were in proximal colon, but by 2001 proximal CRC accounted for 50% of total CRC in females. In contrast, only 41% of CRC in males were in the proximal colon by 2001. 7) In both sexes, there was a marked age-related increase in CRC incidence and increase in proportion of proximal CRC, which did not differ significantly based on sex. Conclusion: In U.S., males continued to have higher incidence of CRC than females throughout the 29-year study period between 1973-2001. The females had significantly higher proportion of CRC in the proximal colon throughout the study period, and the proportion of proximal CRC progressively increased during the study period. Age was also an important factor affecting both the incidence and distribution of CRC in both sexes.