Evidence has indicated that daily aspirin use reduces cancer risk, especially for colorectal cancer (CRC), but the benefit of alternate-day dosing is unclear. In a long-term observational follow-up study of a randomized trial in more than 33,600 women, use of alternate-day low-dose aspirin was associated with a reduced risk for CRC. Although the study limitations included that not all women received extended follow-up and ascertainment bias could not be ruled out, these data indicate a positive effect for low-dose alternate-day aspirin use for CRC prevention.