Observational studies and randomized clinical trials that have looked at the effect of hormone replacement therapy (HRT) on the risk of colorectal cancer are reviewed. Nine cohort studies in this area have included a total of over 2700 cases of colorectal cancer. Most of these studies found a relative risk (RR) of around or below unity. Of 15 case-control studies, with a total of over 7300 cases, six reported a 20-40% risk reduction among women who had ever used HRT. With reference to randomized clinical trials, in the Women's Health Initiative (WHI) study, after seven years of follow-up, 45 cases of colorectal cancer were observed in the combined HRT group versus 67 in the placebo group, corresponding to a RR of 0.63. A combined reanalysis of data from both the WHI and the Heart and Estrogen Progestin Replacement Study (HERS) included 56 cases in the combined HRT group and 83 cases in the placebo group (pooled RR = 0.64). However, in the WHI study cancers diagnosed in the HRT group were more advanced and there were more positive lymph nodes. Furthermore, among women in the WHI who had had a hysterectomy, there was no difference at the eight-year follow-up in the incidence of colorectal cancer between those in the estrogen-only arm of the trial (n = 61) and those in the control group (n = 68).