Background: Routine screening reduces colorectal cancer mortality, but screening rates fall below national targets and are particularly low in underserved populations. Objective: To compare the effectiveness of a single text message outreach to serial text messaging and mailed fecal home test kits on colorectal cancer screening rates. Design: A two-armed randomized clinical trial. Participants: An urban community health center in Philadelphia. Adults aged 50–74 who were due for colorectal cancer screening had at least one visit to the practice in the previously year, and had a cell phone number recorded. Interventions: Participants were randomized (1:1 ratio). Individuals in the control arm were sent a simple text message reminder as per usual practice. Those in the intervention arm were sent a pre-alert text message offering the options to opt-out of receiving a mailed fecal immunochemical test (FIT) kit, followed by up to three behaviorally informed text message reminders. Main Measures: The primary outcome was participation in colorectal cancer screening at 12 weeks. The secondary outcome was the FIT kit return rate at 12 weeks. Key Results: Four hundred forty participants were included. The mean age was 57.4 years (SD ± 6.1). 63.4% were women, 87.7% were Black, 19.1% were uninsured, and 49.6% were Medicaid beneficiaries. At 12 weeks, there was an absolute 17.3 percentage point increase in colorectal cancer screening in the intervention arm (19.6%), compared to the control arm (2.3%, p < 0.001). There was an absolute 17.7 percentage point increase in FIT kit return in the intervention arm (19.1%) compared to the control arm (1.4%, p < 0.001). Conclusions: Serial text messaging with opt-out mailed FIT kit outreach can substantially improve colorectal cancer screening rates in an underserved population. Trial Registration: clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT03479645) [ABSTRACT FROM AUTHOR]