Little is known about the effects of various types, modes, and routes of hormone replacement therapy (HRT) on the risk of colorectal cancer (CRC) among postmenopausal women. We conducted a population-based case-control study with validation of self-reported hormone use and no upper age limit. In 1,456 postmenopausal women aged 45-94 years (546 cases, 910 controls), the use of HRT was associated with reduction in CRC risk among ever users (adjusted odds ratio (OR) 0.65, 95% confidence interval 0.50-0.84), current users, and recent users. There was no evidence that risk reduction among current users varies by age. Risk reduction was seen both in estrogen-only therapy (0.42, 0.23-0.78) and in combination therapy (0.60, 0.41-0.87), the latter regardless of the mode of therapy, whether with hormone patches (0.40, 0.17-0.90) or with oral tablets (0.59, 0.39-0.90). In combination with estrogen, progestagens of the norethisterone and levonorgestrel families were associated with strong reduction in CRC risk.