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Severe complications (SC) in colonoscopy represent the most important adverse effect of colorectal cancer screening programs (CRCSP). The objective is to evaluate the risk factors for SC in colonoscopy indicated after a positive fecal occult blood test in population-based CRCSP. The SC (n = 161) identified from 48,730 diagnostic colonoscopies performed in a cohort of all the women and men invited from 2000 to 2012 in 6 CRCSP in Spain. A total of 318 controls were selected, matched for age, sex and period when the colonoscopy was performed. Conditional logistic regression models were estimated. The analysis was performed separately in groups: immediate-SC (same day of the colonoscopy); late-SC (between 1 and 30 days after); perforation; and bleeding events. SC occurred in 3.30‰ of colonoscopies. Prior colon disease showed a higher risk of SC (OR = 4.87). Regular antiplatelet treatment conferred a higher risk of overall SC (OR = 2.80) and late-SC (OR = 9.26), as did regular anticoagulant therapy (OR = 3.47, OR = 7.36). A history of pelvic-surgery or abdominal-radiotherapy was a risk factor for overall SC (OR = 5.03), immediate-SC (OR = 8.49), late-SC (OR = 4.65) and perforation (OR = 21.59). A finding of adenoma or cancer also showed a higher risk of overall SC (OR = 8.71), immediate-SC (OR = 12.67), late-SC (OR = 4.08), perforation (OR = 4.69) and bleeding (OR = 17.02). The risk of SC doesn't vary depending on the type of preparation or type of anesthesia. Knowing the clinical history of patients such as regular previous medication and history of surgery or radiotherapy, as well as the severity of the findings during the colonoscopy process could help to focus prevention measures in order to minimize SC in CRCSP.