Children with medical conditions often experience a combination of positive and negative social interactions with parents and friends. Adult research examining cross-domain buffering effects has documented that supportive social ties can make up for shortcomings in other social relationships. This study examined whether negative effects of strained relationships with loved ones can be buffered when children feel supported by individuals in different support networks (i.e., cross-domain buffering effects). Children with Type I diabetes (n = 56), chronic asthma (n = 54), and cystic fibrosis (n = 17) completed questionnaires during an outpatient hospital visit that assessed perceptions of support and strain from parents and friends, quality of life, self-concept, and emotional/behavioral difficulties. Parental strain was conceptualized as parental overprotection and parental rejection. Hierarchical regression analyses showed that friend support buffered the adverse effects of parental strain on child quality of life, self-concept, and emotional/behavioral difficulties. Interestingly, parental support did not buffer the negative effects of experiencing strained relationships with friends; only main effects on outcome were found. These findings partially support our hypotheses of cross-domain buffering. In this study, friendships were a protective factor for children who experienced strained relationships with parents. In contrast, although parent support had a direct impact on child outcome, it did not make up for feeling rejected by friends. Because close relationships are often strained during medical stressors, findings underscore the importance of promoting social connectedness in chronically ill children to maximize opportunities for experiencing positive social relationships.