Substance use and misuse (SUM) and the relation to physical activity/exercise/athletic participation (sport factors) and scholastic achievement are rarely studied in Croatia. The aim of this study was: (1) to investigate the SUM habits in Croatian adolescents (17-18 years of age, 254 males, and 218 females), and (2) to study potential gender-specific interrelationships between scholastic and sport factors in relation to SUM. The testing was done using an extensive, anonymous, self-administered questionnaire that consisted of scholastic variables, sport factors, and SUM data. Descriptive statistics, counts, and proportions were calculated. Gender differences were established using the Kruskal-Wallis test. Gender-specific correlations within and between studied variables were established using the Spearman's correlation. The incidence of smoking habits and alcohol consumption among Croatian adolescents was alarming, and a serious intervention program should be developed to address this issue. Educational achievement was negatively related to SUM, with no gender-specific relationships. The data indicated some "protective" effects of the sport factors against SUM in boys, but a significant positive correlation between alcohol drinking and sport participation in girls was also noted.