Background: Previous investigations have shown that low academic achievers are more likely to smoke cigarettes, drink alcohol, and use marijuana and other illicit drugs. This study investigated the relationship between academic performance and substance use among public high school students in Mississippi. Methods: The sampling frame for the 2003 Mississippi Youth Risk Behavior Survey was obtained from the Mississippi Department of Education. A 2-stage cluster sample design produced a representative sample of Mississippi students in grades 9-12 who attended public schools. During the spring 2003, 34 of the 45 sampled schools (75.6%) participated. Results: A total of 1488 from the 1672 sampled students (89.0%) completed an 87-item questionnaire (overall response rate 67.3%). Low academic performance (students with mostly Cs or below) during the 12 months preceding the survey was more prevalent among males, non-Hispanic blacks, frequent smokers, binge drinkers, and marijuana users. Logistic regression identified gender, race, frequent smoking, and marijuana use as statistically significant factors associated with increased odds for low academic performance. Adjusted odds ratios were 1.2 for binge drinkers versus other students to 2.6 for non-Hispanic black students versus non-Hispanic white students. Conclusions: The present findings highlight the extensive use of cigarettes, alcohol, and marijuana among Mississippi public high school students. Because poor academic achievers are more prevalent among students who participate in these substance-use behaviors, multifaceted approaches that encourage high levels of academic performance, while dissuading student involvement in risky/problem behaviors, may both improve low levels of academic achievement and reduce behaviors that contribute to poor health in adulthood.