Diario della Salute [My Health Diary] is a school-based program designed to enhance the subjective well-being and health of 12- to 13-year-old students. We hypothesized that providing students with the social and emotional skills to fulfill their potential and deal with common developmental tasks of adolescence (e.g., onset of puberty, identity development, increased responsibilities and academic demands) would result in improved well-being and health. The program comprises five standardized interactive lessons concerning common psychosocial and health issues in adolescence, and two narrative booklets addressed to both students and their parents. We evaluated the effectiveness of the program in terms of the students’ subjective well-being, aggressive behavior, and health behavior. Using a quasi-experimental study design, schools in the intervention group implemented the full program and those in the comparison group received their regular curriculum. We administered measures of the study’s objectives both before and after program implementation. Statistical analyses accounted for within-school clustering, potential socioeconomic and demographic confounding, and pre-implementation levels of these measures. We sampled 62 schools and allocated 2630 students to either an intervention or comparison group. Sociodemographic characteristics and baseline outcomes were balanced across study groups. Unexpectedly, respondents in the intervention group had 0.38 greater mean adjusted score of the WHO/Europe Health Behaviour in School-Aged Children Symptom Checklist instrument than respondents in the comparison group, indicating a reduction in subjective well-being. We did not observe any program effects on aggressive and health behaviors. The apparent reduction in subjective well-being reflected by an increased perception of psychosomatic complaints is suggestive of either increased emotional competence or, potentially, iatrogenic program effects. While greater emotional competence is positively associated with well-being over the course of life, the program in its present form should not be disseminated due to the possibility of adverse unintended effects.