Introduction: Intervention programs targeting suicide in youth have demonstrated positive, albeit modest effects on knowledge, attenuation of stigma and health promotion. 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 to 18 years. While its overall efficacy was confirmed (https://doi.org/10.1186/s12889-023-17557-9), it’s effects in adolescents with different risk profiles remain yet to be determined. Methods: We explored whether program efficacy (with regard to knowledge about mental health, agency and help-seeking intention) differed for students at low, medium and high risk for suicidality. A pre-post within-group comparison trial was designed to evaluate the HEYLiFE suicide prevention program in a convenience sample of n=304 adolescents from five public schools. A total of n=239 adolescents with completed data set were analyzed. Using 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 did improve to a similar degree across all clusters, agency and help-seeking intentions improved in the low- and medium-risk cluster only, but not in the high-risk cluster. Efficacy across time ranged from small to medium effects. Conclusion: Results confirm that the HEYLiFE suicide prevention program is efficacious for the majority of students, but that efficacy is attenuated for students with high levels of suicidality. Consequently, efforts should be enhanced to specifically target individuals displaying the greatest risk for suicide, be it through the adaptation of the program or through individualized add-on formats.