This study examined ethnic differences in substance use and sexual behavior and whether drinking and drug use constitute risk factors for unsafe sexual practices among Native Hawaiian (NH), Caucasian, and Asian/Pacific Islander (API) high school students in Hawaii. A secondary data analysis of the Youth Risk Behavior Survey (1997 and 1999) using a representative sample of 2,657 students in 9-12 grades was performed. Chi-square tests for bivariate associations and multivariate regression analyses were conducted to identify predictors. NHs were more sexually active, initiated sex earlier, and tended to have multiple partners. Alcohol lifetime use was higher in NH, Caucasians, and males. NHs were more likely to initiate drinking by age 12 and engage more in episodic drinking. Non-episodic or episodic drinkers and students who use drugs were at risk to engage in sexual activity, have multiple partners, and use alcohol/drugs during sex. Risk was two times higher for substance use during sex if drinking was initiated at age 10 or younger compared to 15 years or older. Compared to abstainers, the risk doubled for lifetime multiple partners if drinking was initiated at ages 13-14. Overall, females were more sexually active. Because drinking was associated with sexual initiation and risky behavior, adverse effects of alcohol must be addressed in programs targeting underage drinking, thus helping youth delay of minimize sexual activity and prevent other associated problems. Intervention efforts should enhance life skills that endorse abstinence from alcohol and drug use.