Youth who experience alcohol-related problems are at increased risk for developing alcohol dependence. Identifying factors associated with adolescent alcohol-related problems is essential, but most studies have focused on risk factors or a limited number of protective factors, with little attention to sex differences. We assessed the prospective association between 17 assets and alcohol-related problems among male and female youth. A 4-year cohort study with 1, 111 youth living in randomly-selected census tracts in the Oklahoma City Metropolitan Area was conducted. Follow-up for the current study began at wave 2 (2004/2005; N = 1079). Seventeen assets at the individual-, family-, and community-levels were measured. Five questions documented alcohol-related problems in the past 12 months. Generalized linear mixed models evaluated the prospective influence of assets on alcohol-related problems, separately for males and females. Models controlled for age, race/ethnicity, family structure, and parental income. Overall, females had more assets than males, but the protective influence of assets on alcohol-related problems over time was stronger for males. Six assets uniquely protected males (responsible choices [AOR = 0.58, 95% CI = 0.36-0.94], educational aspirations [AOR = 0.54, 95% CI = 0.31-0.93], parental monitoring [AOR = 0.41, 95% CI = 0.27-0.64], community involvement [AOR = 0.57, 95% CI = 0.34-0.97], use of time for groups/sports [AOR = 0.64, 95% CI = 0.42-0.97], and school connectedness [AOR = 0.51, 95% CI = 0.34-0.77]), and 3 uniquely protected females (general self-confidence [AOR = 0.62, 95% CI = 0.40-0.96], good health practices [AOR = 0.67, 95% CI = 0.47-0.95], and relationship with mother [AOR = 0.53, 95% CI = 0.36-0.80]). Strengthening youth assets across multiple domains may decrease alcohol-related problems for both males and females; however, gender-specific approaches to asset building are also warranted.