Sport participation is considered as a factor of potential influence on illicit drug misuse (IDM) in adolescence, but there is an evident lack of studies which prospectively investigated this problem. This study aimed to prospectively investigate the sports-related factors related to IDM and the initiation of IDM among older adolescents. The participants were 436 adolescents (202 females; 16 years old at study baseline). They were tested at baseline and follow-up (two years later). The predictors included variables associated with different facets of sports participation and success in sports. The criteria were (i) baseline IDM, (ii) follow-up IDM, and (iii) initiation of IDM between baseline and follow-up. Crude and adjusted (controlled for parental conflict, age, socioeconomic status, and gender) logistic regressions were applied to establish correlations between predictors and criteria. There were higher odds for baseline IDM in adolescents who quit individual sports (OR: 4.2, 95% CI: 1.3-13.9), who had better competitive sports achievements (OR: 1.8, 95% CI: 1.0-3.3), and those involved in sports for a longer time (OR: 1.6, 95% CI: 1.0-2.5). The IDM at follow-up was more prevalent in adolescents who were involved in sports for a longer time (OR: 1.7, 95% CI: 1.1-2.6). Initiation of drug use was predicted by longer experience in sports (OR: 1.8, 95% CI: 1.1-3.1). Sports-related factors were more negatively than positively related to illicit drug use. Most probably, the transition from junior to senior level in sports put specific stress on those adolescents who were highly committed to sports until that time, but who then had to question their own sports abilities and future potential in sports. Sport-authorities should be informed on established results and specific public-health efforts aimed at preventing IDM in athletic adolescents are urgently needed.