Abstract: Theoretical Background: Suicide is among the leading causes of death for young people and a major public health concern. While intervention programs targeting youth at risk seem promising, more research is warranted to determine what works for whom. The HEYLiFE universal school-based suicide prevention program aims to promote three putative protective factors, namely, knowledge about mental health, agency, and help-seeking intention in students aged 14 years and older. While its overall efficacy was confirmed previously, specific effects in adolescents with different risk profiles remain to be determined. Objective: We explored whether program efficacy differed for students aged 14 – 18 years (mean age M= 16.2 years, SD = 1.2 years) at low, medium, and high risk for suicidality. Method: A pre–post within-group comparison trial was designed to evaluate the HEYLiFE suicide prevention program in a convenience sample of 304 adolescents from five public schools. The data of 218 adolescents (45.2 % female) with completed data sets were analyzed. Using a two-step cluster analysis, we identified three distinct at-risk clusters for suicidality based on self-reported suicidality, depression, impulsivity/carelessness, and avoidance. We then applied a mixed-model analysis of covariance to evaluate program efficacy in these clusters. Results: While knowledge improved to a similar degree across all clusters, agency and help-seeking intentions improved in the low- and medium-risk cluster but not in the high-risk cluster. Efficacy across time ranged from small to medium effects. Conclusion: Our results confirm that the HEYLiFE suicide prevention program is efficacious for the majority of students. The promotion of protective factors among students with different risk profiles is a viable strategy for universal suicide prevention, although efforts are warranted to specifically target individuals exhibiting the greatest risk for suicide.