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The objective of this study was to estimate the relative impact of hospitalization for depressive syndrome (DS) on all causes of hospitalization and characterize individuals more likely to experience hospitalization for DS in the French cohort study, Manif 2000, of patients HIV infected through injection drug use. We selected all patients followed-up to the 24-month visit (C24) who missed no more than one visit. Using medical records, dates and causes of hospitalizations, were collected retrospectively. A Poisson regression model based on generalized estimating equations was used to identify factors associated with hospitalization for DS. During the study period, 223 hospitalizations were recorded for 120 of the 335 selected patients. DS was the second reason for hospitalization after infections, accounting for 14.3% of the total number of hospitalizations. DS was reported in 32 hospitalizations and involved 24 patients, five of them being hospitalized more than once for the same cause. Factors independently associated with hospitalization for DS were history of multiple incarceration (RR = 2.1, 95% CI: 1.0-4.7), polydrug use (RR = 2.6, 95% CI: 1.1 -5.9) and lack of stable relationship (RR = 4.2, 95% CI: 1.6- 11. 1). In the HAART era, DS represents an important cause of hospitalization of HIV-infected injecting drug users, mainly concerning patients presenting no stable relationship and signs of social instability. Scheduled psychiatric consultations for these patients would permit us to identify those for whom major depression might lead to hospitalization and provide them with timely and appropriate care.