This article reports findings from a cohort study that investigated drug injection cessation over an 18-month period among HIV-infected injecting drug users followed up in a clinical setting. At 18th month visit, individuals reporting persistent injection practices were compared with individuals who reported drug injection cessation for at least 12 months. Crude and adjusted odds ratios were used to assess the impact of change in addictive and sexual behaviors, contacts with the drug network, depression, negative life events, clinical status, HIV therapy, and drug maintenance treatment (DMT) on drug injection cessation. After multiple adjustment, a general decrease of addiction practices (alcohol and cannabis) and of unsafe sexual behaviors significantly accompanied injection cessation. Individuals with higher education level, still in contact with the drug network, and not yet treated for their HIV disease were significantly more likely to persist injecting behaviors. These results underscore the importance and the need of monitoring addiction practices and unsafe sexual behaviors among HIV-positive individuals to properly address primary and secondary prevention in the era of highly active antiretroviral treatments (HAART).