Background To answer the question of what bio-psychosocial determinants in infancy, early and middle childhood, and adolescence predict school drop-out in young adulthood, we approached the complex process towards school dropout as a multidimensional, life-course phenomenon. The aim is to find signs of heightened risks of school dropout as early as possible which will eventually help public health workers in reducing these risks. Methods In a case-control design, we used data from both the Preventive Pediatric Primary Care (PPPC) files (that contain information from birth onwards) and additional questionnaires filled out by 529 youngsters, aged 18-23 years, and living in the South-east of the Netherlands. We first conducted univariate logistic regression analyses with school-dropout as the dependent variable. Backward and forward stepwise analyses with the significant variables were done with variables pertaining to the 0 to 4 year period. Remaining significant variables were forced into the next model and subsequently variables pertaining to respectively the 4 to 8, 8 to 12 and 12 to 16 year period were introduced in a stepwise analysis. All analyses were cross-validated in an exploratory and confirmatory random half of the sample. Results One parent families and families with a non-Western background less often attended the health examinations of the PPPC and such less attendance was related to school dropout. The birth of a sibling (OR 0.63, 95% CI 0.43-0.93) in infancy and self-efficacy (OR 0.53, 95% CI 0.38-0.74) in adolescence decreased the odds of school dropout; externalizing behavior (OR 2.81, 95% CI 1.53-5.14) in middle childhood and (sickness) absence (OR 5.62, 95% CI 2.18-14.52) in adolescence increased the risks. Conclusion To prevent school dropout, PPPC professionals should not wait until imminent dropout, but should identify and tackle risk factors as early as possible and actively approach youngsters who withdraw from public health care.