Gender, smoking, and metabolic syndrome (MetS) are important risk factors of colorectal neoplasm. Whether presence of these factors may warrant earlier screening remains unclear. To compare age- and gender-specific risk of colorectal neoplasms in association with smoking and MetS under endoscopic or stool-based screening. Cross-sectional observational study. Screening center in a university hospital in Taiwan. A cohort of 10,884 average-risk individuals who received concurrent screening colonoscopy and fecal immunochemical testing (FIT). First, the prevalence of colorectal neoplasms and positive predictive value of FIT relative to age, gender, smoking, and MetS. Second, the number of colonoscopies needed to detect 1 advanced neoplasm with different strategies. Male smokers aged 40 to 49 years had a significantly higher prevalence of advanced neoplasms and positive predictive value of stool tests than nonsmoking counterparts. The prevalence of advanced neoplasms in concurrent MetS and smoking (6.2%) or smoking alone (3.8%) men aged 40 to 49 years was higher than that of average-risk women aged 50 to 59 years (2.1%) (P = .03 and .04, respectively). The number of colonoscopies needed to detect 1 advanced neoplasm in men aged 40 to 49 years with concurrent MetS and smoking, smoking, MetS, and women aged 50 to 59 years was, respectively, 14.6, 24.8, 39.8, and 47.4 in the colonoscopy scenario and 1.7, 4.6, 5.7, and 8.3 in the FIT scenario. Self-selective bias may exist for subjects voluntarily submitted to health check-ups. MetS and smoking significantly impact both the prevalence of colorectal neoplasms and the diagnostic yields of screening tests in men aged 40 to 49 years. Whether our findings justify earlier screening in this subgroup requires further study.