Adolescents' friendships with other-sex peers serve important developmental functions, but they may also facilitate engagement in problem behavior. This study examines the unique contributions of other-sex friendships and friends' behavior to alcohol use, smoking, and initiation of sexual intercourse among late adolescent girls and boys. A total of 320 adolescents (53% girls; 33% racial/ethnic minorities) provided sociometric nominations of friendships annually in grades 10-12. Friendship networks were derived using social network analysis in each grade. Adolescents and their friends also reported on their alcohol use, smoking, and sexual debut at each assessment. After controlling for demographics, previous problem behavior, and friends' behavior, other-sex friendships in 10th grade were associated with initiation of smoking among girls over the following year, and other-sex friendships in 11th grade were linked with lower levels of subsequent alcohol use among boys. Additionally, friends' smoking and sexual experience in 10th grade predicted the same behaviors for all adolescents over the following year. Other-sex friendships thus appear to serve as a risk context for adolescent girls' smoking and a protective context for adolescent boys' drinking. Promoting mixed-gender activities and friendships among older high school students may be helpful in reducing males' alcohol use, but may need to incorporate additional components to prevent increases in females' smoking. © 2010 The Author(s).