OBJECTIVES: Employment status is a major predictor of health status and living conditions, especially among HIV-infected people, a predominantly working-aged population. We aimed to quantify the risk of work cessation following HIV diagnosis in France in 2004-2010 and to measure the respective burden of HIV-related characteristics and of associated comorbidities on this risk. DESIGN: We used data from a multicenter cohort made of a diversified sample of recently diagnosed HIV-1-infected adults, antiretroviral treatment-naive at baseline in 2004-2008 (ANRS-COPANA cohort). Detailed information on living conditions and clinical and biological characteristics were collected prospectively. METHODS: The risk of work cessation among the 376 working-aged participants employed at baseline was estimated using the Kaplan-Meier method. Characteristics associated with the risk of work cessation were identified using multivariate Cox models. RESULTS: The cumulative probability of work cessation reached 14.1% after 2 years and 34.7% after 5 years. Diabetes, hypertension and, to a lesser extent, signs of depression were associated with increased risks of work cessation after accounting for socio-occupational characteristics [adjusted hazard ratios (95% confidence interval): 5.7 (1.7-18.8), 3.1 (1.5-6.4) and 1.6 (0.9-2.9), respectively]. In contrast, HIV disease severity and treatment and experience of HIV-related discrimination were not statistically associated with the risk of work cessation. CONCLUSION: The risk of work cessation during the course of HIV disease has remained substantial in the most recent period in France. Comorbidities, but not characteristics of HIV disease itself, substantially affect chances of maintaining employment. This provides insights into strategies for limiting the burden of HIV disease for individuals and society.