We analyzed individual and program characteristics associated with participation in an Information and Communication Technologies (ICT)-based substance use preventive intervention in Uruguay, South America. The intervention was directed at ninth- and tenth-grade students in 10 private schools in Montevideo. Participation in the program was non-mandatory and effective participation rates were low. We found that individual characteristics, such as prior heavy engagement with alcohol and opportunity costs of time, were associated with the decision to participate. We also found that sending the participants periodic reminders via e-mail and short message service (SMS) text messages had a positive impact on participation. The lessons from this intervention suggest that participation in non-mandatory Web-based programs aimed at preventing substance use among adolescents could be substantially improved with a more structured, mandatory, and longer intervention.