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Multisystem organ failure (MSOF) is the most important determinant of mortality in acute pancreatitis (AP). Obesity and alcoholic etiology have been examined as potential risk factors for MSOF, but prior studies have not adequately elucidated their independent effects on the risk of MSOF. We aimed to determine the adjusted effects of body mass index (BMI) and alcoholic etiology on the risk of MSOF in subjects with AP. A prospective observational study of 22 centers from 10 countries was conducted. Patients admitted to an APPRENTICE consortium center with AP between August 2015 and January 2018 were enrolled. Multivariable logistic regression was used to estimate the adjusted effects of BMI, etiology, and other relevant covariates on the risk of MSOF. Models were stratified by sex. Among 1544 AP subjects, there was a sex‐dependent association between BMI and the risk of MSOF. Increasing BMI was associated with increased odds of MSOF in males (OR 1.10, 95% confidence interval [CI] 1.04–1.15) but not in females (OR 0.98, 95% CI 0.90–1.1). Male subjects with AP, whose BMIs were 30–34 and >35 kg/m2, had odds ratios of 3.78 (95% CI 1.62–8.83) and 3.44 (95% CI 1.08–9.99), respectively. In females, neither higher grades of obesity nor increasing age increased the risk of MSOF. Alcoholic etiology was independently associated with increased odds of MSOF compared with non‐alcohol etiologies (OR 4.17, 95% CI 2.16–8.05). Patients with alcoholic etiology and obese men (but not women) are at substantially increased risk of MSOF in AP.