BACKGROUND: Improving uptake of colorectal cancer screening has the potential of saving thousands of lives at minimal cost. We compared the effectiveness of automated and live prompts and reminders as part of a mailed fecal immunochemical test (FIT) outreach program. DESIGN AND METHODS: Participants were 1,767 adults aged 50 – 75 who were not up-to-date with colorectal cancer screening recommendations at a participating community health center clinic. In addition to a mailed FIT kit, participants were randomized to receive: (1) a text message prompt and two automated phone call reminders (automated condition); (2) up to three live call reminders (live condition); or (3) a text message prompt, two automated call reminders, and up to three live reminders (combined automated plus live condition). We assessed FIT completion rates in each group 6 months following randomization. KEY RESULTS: Nearly one-third of participants completed an FIT within 6 months. Compared to adults allocated to the automated condition, FIT completion rates were higher in adults allocated to the live condition (32.3% vs. 26.0%; adjusted Difference = 6.3 percentage points, 95% CI [1.1 – 11.4]), and in adults allocated to the combined automated plus live condition (35.7% vs. 26.0%; adjusted Difference = 9.7 percentage points, 95% CI [4.4 −14.9]). The number of kits needed to mail to achieve a completed FIT ranged from 2.8 in the combined automated plus live condition to 3.8 in the automated condition. CONCLUSIONS: Live phone call reminders either alone or in combination with automated prompts and reminders outperformed automated approaches alone. TRIAL REGISTRATION: National Clinical Trial (NCT) Identifier NCT03167125