Background: “Loss-of-only-child family” refers to the family in which the only child died and the mother has passed her child-bearing age. The parents who are unable to reproduce or do not foster other children are known as “shidu parents” in China. This study aimed to estimate the quality of life (QOL) and the mediating role of social support between perceived stress and QOL in Chinese shidu parents.Methods: 502 shidu parents were recruited in Shenyang city. Shidu parents were asked to complete a questionnaire including the MOS item short from health survey (SF-36), the Perceived Stress Scale-10 (PSS-10) and the Functional Social Support Questionnaire (FSSQ). Hierarchical linear regression was performed to assess the associations among perceived stress, social support and QOL. Asymptotic and resampling strategies were used to explore the mediating role of social support.Results: The mean score of PCS and MCS was 64.83 ± 22.66 and 59.36 ± 21.83, respectively. Perceived stress was found to be negatively associated with both PCS (β=-0.21, p < 0.001) and MCS (β=-0.28, p < 0.001), while social support was positively associated with both PCS (β = 0.32, p < 0.001) and MCS (β = 0.32, p < 0.001). For shidu parents, the proportion of mediation of social support between perceived stress and QOL was 36.85% for PCS and 29.45% for MCS, respectively.Conclusions: Perceived stress was associated with QOL and social support had a partially mediating effect between perceived stress and QOL in Chinese shidu parents. Low PCS and MCS of shidu parents highlight the need of timely developing interventions to reduce stress and reinforce social support to further improve their QOL.