Given the high rates of depression among lesbian, gay, bisexual, and queer (LGBQ) college students, it is important to examine both risk and protective factors in this population. Using a national online sample of 568 LGBQ college students (M age = 20.59 years), we examined the direct relations between sexual orientation-based (LGBQ) microaggressions and internalized heterosexism and depression. We also considered the moderating/buffering roles of positive peer-group relations and involvement in LGBQ campus activities in these links. Results showed that LGBQ microaggressions and internalized heterosexism were positively related to depression at the bivariate level. Hierarchical multiple regression analysis showed that positive peer-group relations moderated the relation between internalized heterosexism and depression. Internalized heterosexism predicted depression for students with low levels of positive peer-group relations, but not for those with moderate or high levels. We also found a conditional direct effect, where LGBQ microaggressions predicted depression, and this effect was stronger for those with high involvement in LGBQ campus activities. Our findings underscore the importance of attending to experiences of minority stress when working with LGBQ college students presenting with depression and helping them to increase positive peer-group relations while considering the potential costs and benefits involved in participating in LGBQ campus activities.