22q11.2 deletion syndrome is a rare multisystem genetic disorder with over 200 associated characteristics, occurring in various combinations and severity. Extensive biomedical research has been undertaken on 22q11.2 deletion syndrome, however, there is a dearth of research on families' experiences of managing a family member with this condition. The complex and at times serious phenotypical presentation of the syndrome can make the management of the condition difficult for families. The aim of this mixed method explanatory sequential study was to investigate family hardiness as a resilience factor for adaptation in families of children with 22q11.2 deletion syndrome from parents' perspectives. We found that adaptation scores increased by 0.57 points (95% CI: 0.19-0.94) for every one-point increase in family hardiness score. Qualitative results indicated that acceptance of the child's diagnosis and support positively influenced hardiness whereas fears about the future and their experiences of loss negatively influenced hardiness.