Rejection sensitivity (RS) refers to the tendency to anxiously expect, readily perceive, and overreact to experiences of possible rejection. RS is a clear risk factor for psychological maladaptation during early adolescence. However, there is growing evidence of significant heterogeneity in the psychological correlates of RS. To investigate when RS poses the greatest psychological risk during early adolescence, this study examines mutual best friendship involvement (or lack thereof) and the best friends’ RS as potential moderators of the associations between RS and psychological difficulties. Participants were 150 7th grade students (58 boys; M age = 13.05 years) who nominated their best friends, and reported on their RS, social anxiety, and self-esteem. Results from a series of hierarchical multiple regression analyses indicated that mutual best friendship involvement and best friends’ RS were both significant moderators when fear of negative evaluation (a type of social anxiety) served as the dependent variable. The association between RS and fear of negative evaluation was stronger for adolescents without mutual best friends than adolescents with mutual best friends. In addition, the association between RS and fear of negative evaluation was the strongest for adolescents whose best friends were highly rejection sensitive (relative to adolescents whose best friends were moderately or low in RS). Findings highlight the importance of considering best friendships in studies of RS and strongly suggest that, although having mutual best friendships may be protective for rejection sensitive adolescents, having a rejection sensitive best friend may exacerbate difficulties. The significance of friends in the lives of rejection sensitive adolescents is discussed as well as possible applied implications of the findings and study limitations.