This article reviews the relationship of oxidative stress with nucleoside reverse transcriptase inhibitor (NRTI)-induced toxicity and suggests how oxidative stress may participate in NRTI-mediated toxicity. NRTIs are pro-drugs that require intracellularphosphorylation to their 5′ triphosphates by cellular kinases to inhibit viral and mitochondrial DMA (mtDNA) replication. NRTIs in highly active antiretroviral therapy have decreased morbidity and mortality, but side effects can be limiting after prolonged use. These side effects may be linked through mitochondrial dysfunction arising from altered mtDNA replication and oxidative stress via destruction of elements of mtDNA replication, decreased oxidative phosphorylation, and cellularfunction. Although oxidative stress is associated with NRTI therapy, there is still debate about whether it plays a direct role in NRTI-induced toxicity. The impact of oxidative stress on cardiovascular disease is likely to increase because patients with HIV infection are living longer as a result of effective antiretroviral therapy.