Background: Abdominal pain after ERCP is common, and although it is frequently nonspecific and self-limited, it may provoke concern for complications and thus distress both patients and physicians. Carbon dioxide (CO2) insufflation during ERCP may reduce abdominal distension in comparison to insufflation of air, resulting in less pain. Objective: To compare the incidence and severity of post-ERCP pain in patients receiving CO2 versus air insufflation during ERCP. Design: Randomized, double-blind, controlled trial. Setting: University medical center. Patients: This study involved consecutive patients presenting for ERCP, excluding those with significant preprocedure pain or obstructive lung disease. Intervention: Randomization to insufflation with air or CO2; all other care was identical. Main Outcome Measurements: Pre-ERCP and post-ERCP pain and nausea were assessed by using a 0 to 10 visual analogue scale. Patient waist circumferences were measured before and after procedures. Results: One hundred patients (82 outpatients, 51 women, mean age 54.4 years, 50 randomized to CO2) completed the study. The CO2 and air groups were similar in regard to demographics, indication for ERCP, and procedure duration. The mean pain score 1 hour post-ERCP was higher with air than with CO2 insufflation (1.9 vs 0.7, P = .01). Similarly, the incidence of any pain at 1 hour post-ERCP was higher with air than with CO2 (48% vs 28%, P = .04). The mean increase in waist circumference was greater with air than with CO2 (2.1 cm vs 0.3 cm, P = .003). Adverse events were infrequent and did not differ by group. No serious cardiopulmonary complications occurred. Limitations: Single-center, selected patient population. Conclusion: Insufflation of CO2 during ERCP reduces postprocedure pain and abdominal distension in comparison to insufflation of air. The use of CO2 in deeply sedated, prone patients appears to be safe.