Objectives To investigate the longitudinal association between frailty and health-related quality of life (HRQoL) in older adults and to examine whether family functionality moderates the association between frailty and HRQoL. Methods It’s a longitudinal observational study. The sample was drawn from three waves (2006, 2010, and 2015) of the Health, Well-Being, and Aging Study (Saúde, bem-estar e envelhecimento; SABE) collected in São Paulo, Brazil with adults aged 60 years and older. HRQoL was based on the Short Form (SF-12) Health Survey, from which the physical component score (PCS) and mental component score (MCS) were obtained. Frailty status was determined according to the Fried frailty criteria. Family support was measured using the family APGAR instrument. Mixed efects linear regression was used to determine the associations of frailty on longitudinal changes in HRQoL and to examine whether family functionality attenuates this association. Results Being frail was negatively associated with MCS and PCS scores. Familiar functionality was found to be a protective factor for MCS only. Conclusions These fndings are innovative and make an important contribution to the study of HRQoL among older adults in developing countries.