Twenty-one medical students with an average age of 23.3 +/- 1.5 years and no family history of large bowel cancer had a rectal biopsy taken for in vitro incorporation of tritiated thymidine (3HTdR). The number and position of labeled epithelial cells in this group was compared with an older control group of 12 and two groups of individuals at high risk for colon cancer. The latter were (1) 18 young asymptomatic individuals from familial colon cancer families without polyposis with a 50% risk for colon cancer, average age 24.1 +/- 3.7; and (2) 17 older individuals with the same genetic background and risk factor, average age 53.8 +/- 10.2 years. A group of 20 young individuals from cancer-free branches of familial colon cancer kindreds with a 25% risk for colon cancer, average age 23.1 +/- 3.6, also was studied. No overall differences in labeling index (LI) were found among the young groups, i.e., the control versus the low risk or high risk. The range of LI values was narrow regardless of risk. However age was associated with a significant increase in LI as observed among older controls and the 50% risk group as compared to younger persons; the range of LI values was wider among the older groups regardless of risk. Concerning the distribution of DNA-synthesizing cells, young controls had significantly more S-phase cells in the lower third of the crypts than either young high-risk or low-risk groups (P less than 0.05). Similarly, young controls had significantly fewer labeled cells in the middle third than the young high-risk group and young controls had significantly fewer S-phase cells in the upper third than did young low-risk or high-risk groups. When young and old members of the same group were pooled, the control group had the highest percentage of labeled cells in the lower third of the crypt (62.5%) which was significantly higher than both the low-risk (53.7%) and the pooled high-risk groups (51.6%). For the upper third of the glands, the low-risk (7.6%) and the pooled high-risk groups (6.8%) were significantly different from the controls (3.3%). Thus initial risk for colon cancer is more related to the distribution of S-phase cells than to their number, i.e., LI. Risk appears to be related to more DNA-synthesizing cells in the upper crypt, an indication that relatively early on in life the DNA switch-off mechanism shows signs of being defective.