This article aims to estimate the prevalence of musculoskeletal disorders (MD) on the adult population of Campinas, São Paulo, Brazil, verifying associated demographic and socioeconomic factors, and to analyze their impact on Health-Related Quality of Life (HRQoL) according to sex. A population-based study was conducted with 2,166 individuals using data from the ISACamp 2014/15. The Medical Outcomes Study SF-36-Item Short Form Health Survey (SF-36) was used to measure HRQoL according to MD. Prevalence ratios (PR) were estimated by Poisson regression. Musculoskeletal disorders had a prevalence of 8.5% (6.7% tendonitis and 2.7% work-related musculoskeletal disorders - WMSD). Results showed a higher prevalence of musculoskeletal disorders in women, active or on leave due to illness, and in individuals with higher education levels. Moreover, reduced HRQoL scores were observed in 6 of the 8 domains, due to MD. The mental component and physical component showed greater impairment respectively among women and men after self-reported WMSD. These findings point to substantial damage from musculoskeletal disorders on the population's HRQoL. WMSD affect the HRQoL of men and women distinctly.