OBJECTIVES: Sessile serrated adenoma (SSA) was recently recognized as a separate pathway that accounts for 10-35% of colorectal cancers (CRCs).  Current CRC screening tests exhibit inferior performance detecting SSAs as compared to other lesion types.  Most existing CRC models do not include the SSA pathway; thus, the cost effectiveness of CRC screening in the face of inferior SSA detection remains uncertain.  We developed a novel CRC model that incorporates the SSA pathway to evaluate the cost-effectiveness of various screening strategies. METHODS: We modeled CRC progression in a simulated cohort of 100,000 individuals from age 50 to 75 that were representative of the general US population.  We investigated several CRC screening strategies within this cohort: colonoscopy every ten years (Q10 COLO); fecal immunochemical testing (FIT) every one, two, or three years (Q1 FIT, Q2 FIT or Q3 FIT); and a hybrid strategy of colonoscopy every ten years with FIT one, two, or three years after negative colonoscopy (COLO/FIT 1, COLO/FIT 2, COLO/FIT 3).  The primary outcomes were cancer incidence, medical cost, quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio (ICER) per QALY.  We assumed full screening compliance.  All economic outcomes were discounted at 3% per year. RESULTS: All screening strategies were cost saving compared to no screening.  The COLO/FIT 2 hybrid strategy reduced cancer incidence the most (59% compared to no screening) and gained the most QALYs compared to no screening (15,200 QALYs for every 100,000 people).  Compared with the standard Q10 COLO strategy, COLO/FIT hybrid strategies produced ICERs of approximately $3,300 per QALY. CONCLUSIONS: Despite the comparatively poor performance of colonoscopy and FIT in detecting SSAs, our simulation results suggested that CRC screening would save costs and increase QALYs.  Hybrid screening strategies with colonoscopy and FIT were cost-effective compared to screening with colonoscopy alone.