Recent reports of the increase in peripheral blood gamma delta T cells in HIV+ patients prompted us to examine the gamma delta T cell system in rhesus monkeys (Macaca mulatta) and the responses of these cells to SIV infection. Our results reveal differences in the gamma delta T cell subset composition and their expression of CD8 in the peripheral blood of monkeys and humans. The outgrowth of simian gamma delta T cells in response to Daudi cells is similar to that in humans, but the exposure to IL-2 stimulates preferentially the simian V delta 1 subset rather than the V gamma 9/V delta 2 subset as found in humans. Upon SIV infection of the monkeys, we observed a transient increase of the percentage of total gamma delta T cell and the V gamma 9 subset. gamma delta T cells from infected animals also express more activation markers such as CD69, CD44 and the memory marker CD45RO. However, they respond to a lesser degree to Daudi or IL-2 stimulation in the outgrowth experiments compared with uninfected animals, although the subset composition of total gamma delta T cells is similar in infected and uninfected animals. The results clearly indicate that gamma delta T cells in rhesus monkeys are influenced by SIV infection. The detailed analysis of the gamma delta T cell response to SIV infection can serve as a model for understanding human gamma delta T cell responses to HIV infections.