It has been speculated that infection with HIV-1 may lead to a significant increase in turnover, and subsequent exhaustion, of immune repopulation. Given that telomeric DNA is lost on mitotic replication, telomere lengths can be used as an indirect gauge of this rate. We have analyzed the mean telomere restriction fragment lengths in peripheral blood mononuclear cells (PBMC) from 31 patients with established, though mainly untreated, HIV infection and found them to be no different than those among healthy controls. Our results are in line with several findings in CD4+ cell fractions but contradict a previous report suggesting that telomere shortening contributes to immune failure. Interestingly, after approximately 2 years of subsequent aggressive antiretroviral treatment we found a telomere reduction corresponding to a loss of about 250 base pairs per year; this is roughly tenfold above that predicted from healthy individuals. This could partly result from nucleoside analogue inhibition of the natural telomere replacement enzyme, telomerase-a reverse transcriptase inducible in certain hematopoietic cells. However, this may also indicate accelerated cell replacement on initiation of optimal therapeutic regimes or result from changes in the composition of the PBMC pool. These results suggest careful monitoring of telomere lengths during long-term HAART.