Social skills group training (SSGT) is a frequently used behavioral intervention in autism spectrum disorder (ASD), but the effects are moderate and heterogeneous. Here, we analyzed the effect of polygenic risk score (PRS) and common variants in gene sets on the intervention outcome. Participants from the largest randomized clinical trial of SSGT in ASD to date were selected (N = 188, 99 from SSGT, 89 from standard care) to calculate association between the outcomes in the SSGT trial and PRSs for ASD, attention-deficit hyperactivity disorder (ADHD), and educational attainment. In addition, specific gene sets were selected to evaluate their role on intervention outcomes. Among all participants in the trial, higher PRS for ADHD was associated with significant improvement in the outcome measure, the parental-rated Social Responsiveness Scale. The significant association was due to better outcomes in the standard care group for individuals with higher PRS for ADHD (post-intervention: β = −4.747, P = 0.0129; follow-up: β = −5.309, P = 0.0083). However, when contrasting the SSGT and standard care group, an inferior outcome in the SSGT group was associated with higher ADHD PRS at follow-up (β = 6.67, P = 0.016). Five gene sets within the synaptic category showed a nominal association with reduced response to interventions. We provide preliminary evidence that genetic liability calculated from common variants could influence the intervention outcomes. In the future, larger cohorts should be used to investigate how genetic contribution affects individual response to ASD interventions.