BACKGROUND: Reduced health-related quality of life in the physical domain (HRQOL(physical)) has been reported to increase risks for cardiovascular disease (CVD); however, the mechanism underlying this phenomenon is still unclear. The autonomic nervous system (ANS) that connects the body and mind is a biologically plausible candidate to investigate this mechanism. The aim of our study is to examine whether the HRQOL(physical) independently contributes to heart rate variability (HRV), which reflects ANS activity. METHODS: We recruited 329 physically and mentally healthy adults. All participants completed Beck Anxiety Inventory, Beck Depression Inventory and World Health Organization Questionnaire on Quality of Life: Short Form-Taiwanese version (WHOQOL-BREF). They were divided into groups of individuals having high or low scores of HRQOL(physical) as discriminated by the quartile value of WHOQOL-BREF. We obtained the time and frequency-domain indices of HRV, namely variance (total HRV), the low-frequency power (LF; 0.05-0.15 Hz), which may reflect baroreflex function, the high-frequency power (HF; 0.15-0.40 Hz), which reflects cardiac parasympathetic activity, and the LF/HF ratio. RESULTS: There was an independent contribution of HRQOL(physical) to explaining the variance in HRV after excluding potential confounding factors (gender, age, physical activity, alcohol use, depression and anxiety). Compared with the participants with high levels of HRQOL(physical), those with low levels of HRQOL(physical) displayed significant reductions in variance and LF. CONCLUSIONS: This study highlights the independent role of low HRQOL(physical) in contributing to the reduced HRV in healthy adults and points to a potential underlying mechanism for HRQOL(physical) to confer increased risks for CVD.