Background Mailed fecal immunochemical testing (FIT) programs can improve colorectal cancer (CRC) screening rates, but health systems often vary implementation (i.e., adapt) these programs for their organizations. A health insurance plan implemented a mailed FIT program (named BeneFIT) and allowed participating health systems to adapt the program. This mixed-methods study explored which program adaptations might have achieved higher screening rates.Methods We used a multi-method approach. First, we conducted a descriptive analysis of CRC screening rates by key health system characteristics and program adaptations. Second, we applied Configurational Comparative Methods (CCMs) to determine potential explanatory factors consistent with higher screening rates. The main outcome measure was CRC screening rates.Results Seventeen health systems took part in at least one year of BeneFIT. The overall screening completion rate was 20% (4–28%) in Year 1, and 25% (12–35%) in Year 2 of the program. Health systems that used two or more adaptations had higher screening rates, and no single adaptation clearly led to higher screening rates. In Year 1, smaller systems (having < 2 clinics) with phone reminders (n = 2) met the implementation success threshold (≥ 19% screening rate) while larger systems were successful when offering a patient incentive (n = 4), scrubbing mailing lists (n = 4), or allowing mailed FIT returns with no other adaptations (n = 1). In Year 2, large systems (> 2 clinics) were successful with a phone reminder (n = 4) or a patient incentive (n = 3). Of the 10 systems that implemented BeneFIT in both years, seven improved in Year 2.Conclusions Health systems can choose between many adaptations and successfully implement a health plan’s mailed FIT program. Screening completion rates are positively associated with the number of adaptations implemented by a health system. Health system size emerged as an important contextual factor, with different solutions for larger than smaller health systems.Contributions to the Literature· Our paper analyzes adaptations that enable health care providers to implement mailed fecal immunochemical testing (FIT) programs in delivery systems.· Our results explore which adaptations made by health systems to mailed FIT programs are related to screening rate improvements. Our analysis shows that a health system’s organizational characteristics in combination with the adaptations themselves may affect resulting CRC screening rates and implementation.· Our paper describes different pathways that health care organizations can use to implement CRC screening outreach to improve the health of their populations. We show results of implementation flexibility and customizing CRC screening outreach to particular clinic environments.