Background: Hispanic adults in the United States have low colorectal cancer (CRC) screening rates and are more likely than non-Hispanic adults to be diagnosed with advanced-stage CRC. We evaluated the reach, effectiveness, adoption, implementation and maintenance (RE-AIM) of a novel multilevel decision support and navigation intervention (DSNI) designed to increase CRC screening among Hispanic primary care patients.Methods: The trial enrolled 400 consented participants from a health system sampling frame of 2,720 Hispanic patients eligible for CRC screening in five primary care practices. We randomized 203 patients to receive a mailed standard intervention (SI Group) that included informational material, a fecal immunochemical test kit, a reminder versus 197 patients who received the SI plus a telephone screening DSNI (DSNI Group). We assessed DSNI effects using health system and study administrative data.Results: 1) Reach: DSNI delivery reached 84% of participants. 2) Effectiveness: The DSNI group produced a screening rate that was significantly greater (p < .001) than in the SI group (78% and 43%, respectively). 3) Adoption: All participating primary care practices and patients remained in the study. 4) Implementation: DSNI delivery required an average of 4.1 decision support and navigation call attempts with the total call effort averaging 35 minutes. 5) Maintenance: Health system leaders have acknowledged DSNI benefits and are actively engaged in determining how to sustain DSNI implementation.Conclusion: The DSNI achieved high levels of reach, effectiveness, adoption, and implementation with a modest investment of resources. The project team is addressing the challenge of DSNI maintenance in the health system. Further work is needed to determine intervention effectiveness in other health systems and in the general patient population. Trial Registration: ClinicalTrials.gov identifier : NCT02272244