Patients who have multiple chronic conditions (MCCs) and their informal caregivers experience poorer health-related quality of life (HRQOL). Perceived social support has been shown to influence HRQOL. This study aimed at identifying the differences between patients' and caregivers' physical and mental HRQOL; and determining the association between their perception of social support from different sources, and their own and their dyad partner's HRQOL. Patients with MCCs and their caregivers (345 dyads) were enrolled in a multicenter cross-sectional study conducted in Italy.