Abstract Background The objective of this study was to assess the effectiveness of a Patient Navigation Intervention targeting deprived patients for Colo-Rectal Cancer (CRC) screening participation. Methods A cluster randomized controlled trial was conducted in 5 districts. Peer Lay Patient Navigators were recruited to operate in deprived areas. Eligible participants had to be between 50 and 74 years old, live in these deprived areas and receive an invitation to the nationally organized Colo-Rectal Cancer (CRC) screening during the study period. The theory-driven navigation intervention was deployed for 18 months. A population Health Intervention Research assessment method was used to assess effectiveness and context interaction. The primary criterion was screening participation at 12 months. Results Twenty-four thousand two hundred eighty-one individuals were included inside 40 clusters. The increase in participation in the intervention group was estimated at 23%, (ORa = 1.23, CI95% [1.07–1.41], p = 0.003). For the subgroup of individuals who participated, the time delay to participating was reduced by 26% (ORa = 0.74, CI95% [0.57–0.96], p = 0.021). Main factors modulating the effect of the intervention were: closeness of navigator profiles to the targeted population, navigators’ abilities to adapt their modus operandi, and facilitating attachment structure. Conclusion The ColoNav Intervention succeeded in demonstrating its effectiveness, for CRC screening. Patient Navigation should be disseminate with broader health promotion goals in order to achieve equity in health care. Trial registration clinicaltrials.gov NCT02369757 24/02/2015.