The nucleoside and nucleotide reverse transcriptase inhibitor (N[t]RTI) drug class remains an integral component of effective antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection. However, these drugs are associated with toxicities, through their off-target effects, that may significantly contribute to a number of long-term comorbidities, including coronary artery disease (CAD) and myocardial infarction (MI), recognized to occur with increased frequency in those with HIV undergoing treatment with ART. The contribution of N(t)RTI to CAD and MI may arise either indirectly through induction of metabolic toxicities such as dyslipidemia and insulin resistance, or directly through impact on pathologic pathways involved in development of MI, such as altered platelet responsiveness or endothelial dysfunction. This review focuses on the available data relating to use of individual N(t)RTI drugs and the drug class as a whole and CAD, with a focus on MI.