PURPOSE: To examine the respective and combined impact of "hypothetical" functional impairment (FI) and burden of comorbidities accrual on a 5-year risk of health utility (HU) loss in osteoarthritis (OA). METHODS: Participants of the Knee and Hip Osteoarthritis Long-term Assessment (KHOALA) study with a 5-year follow-up were included. FI, number of comorbidities and HU were measured annually by the WOMAC, Functional Comorbidity Index and Short-Form 6D, respectively. We estimated the population risk of HU loss (PRD: population risk difference, PRR: population risk ratio) under hypothetical FI and comorbidities using the parametric G-formula. Then, mediation analysis investigated the causal mechanism of comorbidities on HU through FI by estimating total, direct and indirect effects. RESULTS: We examined data from 767 patients (68.8% women; 61.6 years). The estimated 5-year risk of HU loss was 47.5% [41.9; 52.2] under natural course and 24.9% [15.5; 34.2] when imposing "Patient acceptable function and No comorbidity" corresponding to a PRD = - 22.6 [- 26.5; - 21.2] and a PRR = 0.5 [0.4; 0.6]. The estimated total risk of HU loss comparing "Two comorbidities" versus "No comorbidity" was significant without mediation effect of FI: Total = 10.1% [6.8; 12.9]; direct = 8.0% [2.7; 13.1]; indirect = 2.1% [- 2.0; 5.2]. CONCLUSIONS: FI and comorbidities are important and independent determinants of HU loss in patient with OA. Half of cases (50%) of HU loss during 5 years could be avoided by preventing comorbidities (30%) and limiting FI under patient acceptable function (20%). Caregivers should additionally pay close attention to the prevention and the treatment of comorbidities in routine management of OA.