Background Medically unexplained physical symptoms (MUPS) are highly prevalent and are associated with frequent health care use (HCU). MUPS frequently co-occur with psychiatric disorders. With this study we examined the longitudinal association between MUPS and HCU over 2 years and the influence of depressive and anxiety disorders and personality traits on this association. Methods We analysed follow-up data from 2045 to 2981 participants from the Netherlands Study of Depression and Anxiety (NESDA), a multisite cohort study. The study population included participants with a current depressive and/or anxiety disorder, participants with a lifetime risk and/or subthreshold symptoms for depressive and/or anxiety disorders and healthy controls. HCU, measured with the Trimbos and iMTA questionnaire on Costs associated with Psychiatric illness (TIC-P), was operationalized as the number of used medical services and the number of associated contacts. MUPS were measured with the Four Dimensional Symptoms Questionnaire, depressive and anxiety disorders with the Composite International Diagnostic Interview and personality traits with the NEO Five-Factory Inventory. Measurements were taken at baseline, 1 and 2 years follow-up. We used generalized estimating equations (GEE), using HCU at all three measurements as (multivariate) outcome. GEE also takes into account the dependency of observations within participants. Results MUPS were positively associated with HCU over 2 years (medical services: RR 1.020, 95 % CI 1.017–1.022; contacts: RR 1.037, 95 % CI 1.030–1.044). Neuroticism and depression had the strongest influence on the associations. After adjustment for these factors, the associations between MUPS and HCU weakened, but remained significant (services: RR 1.011, 95 % CI 1.008–1.014; contacts: RR 1.023, 95 % CI 1.015–1.032). Conclusions Our results show that MUPS were positively associated with HCU over 2 years, even after adjusting for depressive and anxiety disorders and personality traits.