The study examined the mediating effect of internalized shame on the relationship between affiliate stigma and interpersonal anxiety among adolescents with siblings who had autism spectrum disorder (ASD) and the moderated mediating effect of mother-adolescent communication openness. The participants consisted of 139 adolescents (boys 48.9%, high-school students 79.8%) who had siblings with ASD. Interpersonal anxiety, affiliate stigma, internalized shame, and mother-adolescent communication openness were measured using the Social Anxiety Scale for Adolescents (La Greca & Lopez, 1998), the Affiliate Stigma Scale (Mak & Cheung, 2008), the Internalized Shame Scale (Cook, 1988), and the Parent-Adolescent Communication Scale (Barnes & Olson, 1982), respectively. The data were analyzed using descriptive statistics and Pearson’s correlation coefficients. Process Macro Models 4 and 7 were used to examine the mediating effect and the moderated mediating effect. The results indicated that internalized shame mediated the effect of affiliate stigma on interpersonal anxiety among adolescents who had siblings with ASD. However, there was no significant moderated mediating effect of mother-adolescent communication openness on the relationship between affiliate stigma, internalized shame and interpersonal anxiety. These findings suggest that it is necessary to improve social awareness of individuals with ASD and their family members to prevent adolescents who have siblings with ASD from having affiliate stigma and to help them reduce interpersonal anxiety. The results also highlight the importance of counseling programs for adolescents with siblings with ASD as a way of preventing or alleviating their interpersonal anxiety by reducing internalized shame, even where they experience affiliate stigma.