Interactions between combination antiretroviral therapy (CART) and lung cancer treatment are emerging clinical concerns. Among the reasons for that, one can observe the longer survival of human immunodeficiency virus (HIV)-infected patients since introduction of CART and the epidemiologic rising of lung cancer, mainly adenocarcinomas, in this population. In addition, the higher relative risk of lung cancer in HIV-infected patients compared with general population has been recently demonstrated. Patients' demography and disease characteristics differ from the general lung cancer population, although most cases occur in patients with a smoking history: HIV-infected subjects are generally younger and diagnosis frequently made at locally advanced or metastatic stages. The choice of cytotoxic chemotherapy and antiretroviral therapy is essential in the context of lung cancer (1) to minimize potential interactions and life-threatening toxicities particularly through cytochrome P450 interaction, (2) to implement adequate prevention of foreseeable toxicity, and (3) to fully reinforce antineoplastic and antiretroviral efficacy. Pharmacokinetics data and clinical cases pinpoint to potential life-threatening interactions between protease inhibitors/ritonavir and taxanes, vinca alkaloids, as well as the anilinoquinazolines erlotinib and gefitinib and irinotecan. Optimal choice of chemotherapy and CART in HIV-infected patients with lung cancer is an individualized multidisciplinary decision, involving clinical and antiretroviral history, and predicting potential adverse events and interactions.