AbstractIndividuals with a family history of colorectal cancer (CRC) may benefit from early screening with colonoscopy or immunologic fecal occult blood testing (iFOBT). We systematically evaluated the benefit‐harm trade‐offs of various screening strategies differing by screening test (colonoscopy or iFOBT), interval (iFOBT: annual/biennial; colonoscopy: 10‐yearly) and age at start (30, 35, 40, 45, 50 and 55 years) and end of screening (65, 70 and 75 years) offered to individuals identified with familial CRC risk in Germany. A Markov‐state‐transition model was developed and used to estimate health benefits (CRC‐related deaths avoided, life‐years gained [LYG]), potential harms (eg, associated with additional colonoscopies) and incremental harm‐benefit ratios (IHBR) for each strategy. Both benefits and harms increased with earlier start and shorter intervals of screening. When screening started before age 50, 32‐36 CRC‐related deaths per 1000 persons were avoided with colonoscopy and 29‐34 with iFOBT screening, compared to 29‐31 (colonoscopy) and 28‐30 (iFOBT) CRC‐related deaths per 1000 persons when starting age 50 or older, respectively. For iFOBT screening, the IHBRs expressed as additional colonoscopies per LYG were one (biennial, age 45‐65 vs no screening), four (biennial, age 35‐65), six (biennial, age 30‐70) and 34 (annual, age 30‐54; biennial, age 55‐75). Corresponding IHBRs for 10‐yearly colonoscopy were four (age 55‐65), 10 (age 45‐65), 15 (age 35‐65) and 29 (age 30‐70). Offering screening with colonoscopy or iFOBT to individuals with familial CRC risk before age 50 is expected to be beneficial. Depending on the accepted IHBR threshold, 10‐yearly colonoscopy or alternatively biennial iFOBT from age 30 to 70 should be recommended for this target group.