To test the efficacy of a community-based intervention, Empowering Communities for Life (EC4L), designed to increase colorectal cancer (CRC) screening through fecal occult blood test (FOBT) in rural underserved communities in a randomized controlled trial. Participants were randomized into 3 groups (2 interventions and 1 control). Interventions were delivered by community lay health workers or by academic health professionals. The main outcome of interest was return rate of FOBT screening kit within 60 days. Participants included 330 screening-eligible adults. The overall return rate of FOBT kits within 60 days was 32%. The professional group (Arm 2) had the highest proportion of returned FOBTs within 60 days at 42% (n = 46/110), a significantly higher return rate than the lay group (Arm 1) [28%(n = 29/103);P = 0.0422] or control group (Arm 3) [25%(n = 29/117);P = 0.0099]. Thus, one arm (Arm 2) of our intervention produced significantly higher CRC screening through FOBT. Community-based participation partnered with academic health professionals enhanced CRC screening among rural and poor-resourced communities.