Zinc deficiency is the most prevalent micronutrient abnormality seen in human immunodeficiency virus (HIV) infection. Low levels of plasma zinc predict a 3-fold increase in HIV-related mortality, whereas normalization has been associated with significantly slower disease progression and a decrease in the rate of opportunistic infections. Studies in Miami, Florida, indicated that HIV-positive users of illicit drugs are at risk for developing zinc deficiency, at least partially because of their poor dietary intake. Zinc deficiency characterized by low plasma zinc levels over time enhances HIV-associated disease progression, and low dietary zinc intake is an independent predictor of mortality in HIV-infected drug users. The amount of zinc supplementation in HIV infection appears to be critical, because deficiency, as well as excessive dietary intake of zinc, has been linked with declining CD4 cell counts and reduced survival. More research is needed to determine the optimal zinc supplementation level in HIV-infected patients, to prevent further burden on an already compromised immune system.