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Background Prompt detection of colorectal cancer under age 50 (early-onset CRC) is a clinical priority due to its alarming rise. Methods We conducted a matched case-control study of 5075 incident early-onset CRC among U.S. commercial insurance beneficiaries (113 million adults aged 18-64) with ≥2 years of continuous enrollment (2006-2015) to identify red-flag signs/symptoms between 3 months to 2 years before the index date among 17 pre-specified signs/symptoms. We assessed diagnostic intervals according to the presence of these signs/symptoms before and within 3 months of diagnosis. Results Between 3 months to 2 years before the index date, four red-flag signs/symptoms (abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia) were associated with an increased risk of early-onset CRC, with ORs ranging from 1.34 to 5.13. Having 1, 2, or ≥ 3 of these signs/symptoms were associated with a 1.94 (95% CI, 1.76 to 2.14), 3.59 (2.89 to 4.44), and 6.52 (3.78 to 11.23)-fold risk (Ptrend < .001), with stronger associations for younger ages (Pinteraction < .001) and rectal cancer (Pheterogenity=0.012). The number of different signs/symptoms was predictive of early-onset CRC beginning 18 months before diagnosis. About 19.3% of cases had their first sign/symptom occur between 3 months to 2 years before diagnosis (median diagnostic interval: 8.7 months), and around 49.3% had the first sign/symptom within 3 months of diagnosis (median diagnostic interval: 0.53 month). Conclusions Early recognition of red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, or iron-deficiency anemia) may improve early detection and timely diagnosis of early-onset CRC.

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