Health-related quality of life (HRQOL) of caregivers of children with disabilities (CWD) is important for both children's rehabilitation and caregivers' life, but the corresponding attention is far from enough in mainland China. Thus, we investigated the HRQOL of 170 caregivers and related factors in Shanghai. The 12-item Short Form Health Survey (SF-12) was used to measure HRQOL. The potential factors were collected, including child characteristics, caregiver characteristics, and environmental factors. Univariate analysis and multiple linear regression were performed to identify the key factors that could be intervened. Compared with the general population, caregivers of CWD had a slightly higher score on the physical component summary (PCS, 52.57 +/- 8.41), but the score of mental component summary (MCS, 31.58 +/- 7.72) was extremely low. Caregiver's illness condition, family size, and household income were significant factors of physical HRQOL. Caregivers with illness and caregivers living in an extended family were associated with higher mental HRQOL. Whereas these two factors had opposite effects on physical HRQOL. This finding indicated poor mental HRQOL among caregivers of CWD in Shanghai and thus requiring urgent attention and intervention. Improving physical fitness, maintaining family integration, and providing financial support should be considered when developing intervention for this population.