The objective of this study was to evaluate the influence of family, psychosocial, health, demographic, and behavioral characteristics on regular drug use. All the students of 17 randomly stratified public secondary schools in Nairobi were required to complete self-administered sociodemographic and the Drug Use Screening Inventory-Revised (DUSI-R) questionnaires in a cross-sectional descriptive study. All the 1328 students, of whom 58.9% were male, responded to all the questions, giving a response rate of 100%. The mean age of the respondents was 16 years and 78.1% were in boarding school. One third (33.9%) scored positively for substance abuse. Significant correlations were found between several domains of substance abuse and school, class, mode of school attendance, age, and gender. Students abusing drugs have multiple comorbidity of medical, psychological, and social pathologies. There are evidence-based intervention entry points for drug abuse that go beyond mere impartation on knowledge about the harmful effects of drugs.