Abstract Background Musculoskeletal disorders (MSDs) represent a major challenge for occupational and public health, but data are scarce in Switzerland or concentrated on a few sectors of activities. The aim of this study is to provide results on the prevalence and risk and protective factors of MSDs in the general working-age population of the Geneva canton, Switzerland. Methods A cross-sectional analysis was conducted as part of Specchio population-based cohort study. Prevalence and associations between MSDs and sociodemographic variables, individual behaviour (smoking, physical activity, sleep), health conditions (BMI, chronic diseases), physical and psychological risks at work were examined using regression models. The impact of teleworking was also evaluated. Results 2’733 participants took part in the survey, of which 38% were men, and mean age was 50. Overall prevalence of MSDs was 74% among men and 84% among women. 80% of the individuals experience back pain and 56% shoulder pain. Among individuals who experienced MSDs, 55.2% consulted a healthcare professional. The risk factors for MSDs were female sex (OR = 1.95; 95% IC = 1.55-2.28), body mass index (obese) (2.2; 1.51-3.32), lower education (1.77; 0.84-4.37), smoking (1.65; 1.19-2.35), exposure to physical risks (3.54; 2.78-4.51), stress at work (effort-reward imbalance) (3.23; 2.45-4.29) and a poor work-life balance (2.36; 1.88-2.97). The prevalence of MSDs remained high among workers who telework (78% versus 84% in working population). Conclusions This study, carried out in a large population-based cohort, confirmed several risk factors for MSDs. These results will contribute to the implementation of prevention strategies, especially as teleworking has gained in importance in recent years, which may have aggravated workers’ isolation and stress, sedentariness, and poor body posture. Main message: These data confirm the weight of musculoskeletal disorders and will help implementation of prevention health strategies. Key messages • The relationship between psychosocial risks at work and the occurrence of Musculoskeletal Disorders (MSDs) persists even following adjustment for exposure to physical risks and individual risk factors. • The prevalence of musculoskeletal (MSDs) disorders remained high among workers who telework.