OBJECTIVES: We have shown that, in a randomized trial comparing adherence to different colorectal cancer (CRC) screening strategies, participants assigned to either fecal occult blood testing (FOBT) or given a choice between FOBT and colonoscopy had significantly higher adherence than those assigned to colonoscopy during the first year. However, how adherence to screening changes over time is unknown. METHODS: In this trial, 997 participants were cluster randomized to one of the three screening strategies: (i) FOBT, (ii) colonoscopy, or (iii) a choice between FOBT and colonoscopy. Research assistants helped participants to complete testing only in the first year. Adherence to screening was defined as completion of three FOBT cards in each of 3 years after enrollment or completion of colonoscopy within the first year of enrollment. The primary outcome was adherence to assigned strategy over 3 years. Additional outcomes included identification of sociodemographic factors associated with adherence. RESULTS: Participants assigned to annual FOBT completed screening at a significantly lower rate over 3 years (14%) than those assigned to colonoscopy (38%, P<0.001) or choice (42%, P<0.001); however, completion of any screening test fell precipitously, indicating the strong effect of patient navigation. In multivariable logistic regression analysis, being randomized to the choice or colonoscopy group, Chinese language, homosexuality, being married/partnered, and having a non-nurse practitioner primary care provider were independently associated with greater adherence to screening (P<0.01). CONCLUSIONS: In a 3-year follow-up of a randomized trial comparing competing CRC screening strategies, participants offered a choice between FOBT and colonoscopy continued to have relatively high adherence, whereas adherence in the FOBT group fell significantly below that of the choice and colonoscopy groups. Patient navigation is crucial to achieving adherence to CRC screening, and FOBT is especially vulnerable because of the need for annual testing.