This study aimed to determine the prevalence of the use of medicines, particularly over-the-counter medicines (OTC medicines), and to analyse its association with different personal and lifestyle aspects. The study sample was an adolescent population in the Valencian Community (East Spain) aged 14-17 years. A total of 23,349 adolescents from 229 schools completed a questionnaire (response rate 89.54%). We analysed adolescents who were taking prescribed medicines at the time of the questionnaire, and who were users of OTC medicines that had not been prescribed by a doctor for a particular illness. We estimated this association with several personal and lifestyle factors using simple and multivariate analyses and logistic regression. A total of 15.18% of the participants reported that they were taking prescribed medicines when they answered the questionnaire, and 45.38% of the participants reported a frequent use of OTC medicines. Prescribed medicine use is more likely in older adolescents [Relative Prevalence Ratio adjusted by confounding factors (RPRa) 1.05, 95% CI:1.01-1.10], in those who had tried to lose weight by dieting in the last year (RPRa 1.23, 95% CI: 1.11-1.37), in current smokers (RPRa 1.13, 95% CI: 1.02-1.27), in those who had a serious emotional problem (RPRa 1.85, 95% CI:1.60-2.16) and in people who presented a chronic pathology (RPRa 8.24, 95% CI: 7.45-9.11). Respondents who reported a frequent use of OTC medicines were more likely to be older (RPRa 1.03, 95% CI: 1.00-1.06), have tried to lose weight by dieting in the last year (RPRa 1.15, 95% CI:1.06-1.24), be a current smoker (RPRa 1.19, 95% CI:1.10-1.28), have a serious emotional problem (RPRa 1.48,95% CI: 1.31-1.67), and watch TV (RPRa 1.24, 95% CI:1.16-1.32). We noted an extensive use of medicines, especially OTC medicines, in adolescents, and an association with some personal and lifestyle factors. We conclude that prevention and early education of a responsible use of medicines should be a public health priority.