Objective: Chronic diseases are increasingly prevalent and often occur as multimorbidity. This study compares the impact of musculoskeletal disorders (MSKDs) on health and health care costs with other chronic diseases, and assesses the additional impact of MSKDs on these outcomes when occurring as part of multimorbidity. Methods: A household survey in a random Dutch population sample (n = 8,904) yielded information on sociodemographics, presence of 9 physician-confirmed chronic diseases (i.e., musculoskeletal, migraine, diabetes mellitus, cardiovascular, cancer, respiratory, skin, mental, and gastrointestinal), physical component summary (PCS) and mental component summary (MCS) scores of the Short Form 12 health survey, and health care utilization. The independent influence of different diseases and the role of MSKDs with increasing number of morbidities on PCS/MCS and 3-month societal health care costs were explored through multivariable linear and zero-inflated negative binomial regressions, respectively. Results: Twenty percent of all subjects and 56% of those with multimorbidity had an MSKD. MSKDs had the largest impact on PCS (β = −8.37 [95% confidence interval (95% CI) −8.84, −7.89]) but no significant impact on MCS. When MSKDs occurred as part of multimorbidity, an amplification of the adverse effect on PCS but not on MCS was seen, irrespective of the number of comorbidities. MSKDs were responsible for a 2-fold increase in costs (Exp [β] = 2.27 [95% CI 2.08, 2.51]), which was the second highest cost increase of all diseases (after cancer). Significant amplification of costs was seen when MSKDs co-occurred with mental diseases. Conclusion: MSKDs often co-occur with other chronic diseases. In the context of multimorbidity, presence of an MSKD amplifies the impact on physical health, and to a lesser extent on health care costs, but not on mental health.