Objectives To investigate the effect of general practice (GP) and general practitioner (GPR) endorsement for faecal occult blood test (FOBT)-based screening on maintenance of participation in screening over four successive screening rounds. Setting South Australian residents aged ≥50 years. Methods Random selection of four groups (n = 600 per group): one from the Commonwealth electoral roll (ER) and three from the combined patient lists of two collaborating GPs (GP1, GP2, GP3). Subjects were mailed offers to screen using a faecal immunochemical test over four successive rounds, spaced approximately 18 months apart. The GP1 and ER groups were invited to screen without any endorsement from a GPR or medical practice; GP2 invitees received an invitation indicating support for screening from their medical practice; and GP3 invitations were printed on practice letterhead and were signed by a GPR. Results Multivariate analyses indicated that initial participation as well as re-participation over four successive rounds was significantly enhanced in the GP2 (39%, 42%, 45% and 44%) and GP3 groups (42%, 47%, 48% and 49%) relative to the ER group (33%, 37%, 40% and 36%). The analyses also indicated that 60-69 year olds were most likely to participate in all rounds (relative risk [RR] 1.49, 1.39, 1.43 and 1.25), and men were generally less likely to participate than women in all screening rounds (RR 0.86, 0.84, 0.80 and 0.83). Conclusions Associating a GPR or medical practice of recent contact with an invitation to screen achieves better participation and re-participation than does an invitation from a centralized screening unit. Furthermore, enhanced participation can be achieved by practice endorsement alone without requiring actual GPR involvement.