Sulindac is a nonsteroidal anti-inflammatory drug that can provide effective chemoprevention for colorectal cancer. In this study, alternative dosing regimens of sulindac were evaluated for their chemoprevention effectiveness in the azoxymethane-treated A/J mouse model of colorectal cancer. High resolution endoscopic optical coherence tomography was utilized to time-serially measure tumor number and tumor burden in the distal colon as the biological endpoints. Four treatment groups were studied: 1) daily for 20 weeks (Sulindac-Daily), 2) for two weeks, then no sulindac for two weeks, cycle repeated 5 times (Sulindac-2), 3) for ten weeks (“on”), then no sulindac for 10 weeks (“off”) (Sulindac-10), 4) no sulindac (Sulindac-None). Sulindac-2 and Sulindac-Daily had statistically significantly lower final tumor counts and slopes (change in number of tumors per week) when compared with Sulindac-None (p < 0.0001). All of the treatment groups had statistically significantly lower final tumor burdens and slopes when compared with Sulindac-None (p < 0.001). There was a prolonged latency period in the Sulindac-10 group, with no significant difference between the “off” portion of this treatment and Sulindac-None. These results suggest that, while daily doses of sulindac provide the most optimal effects, intermittent doses of sulindac in a 50% duty cycle with an overall four-week period (Sulindac-2 model) can provide highly effective chemoprevention of colorectal cancer in this model. After cessation of sulindac treatment (Sulindac-10 “off”), there is not evidence of either a persistent chemopreventive effect nor a rebound effect.