Mitochondrial:nuclear DNA (mtDNA:nDNA) ratios in blood cells were investigated in relation to selected human immunodeficiency virus antiretroviral drug regimens. Patients (n = 214) continually received a regimen consisting of either (1) saquinavir (SAQ) + ritonavir (RTV) + either nevirapine (NVP) or lamivudine (3TC) (n=32) or (2) SAQ+RTV (+/- either NVP or 3TC) + either stavudine (d4T) (n=127), didanosine (ddI) (n=19), d4T+ddI (n=21), or zidovudine (ZDV) (n=15), for >/=4 months. NVP- or 3TC-only regimens were associated with median mtDNA:nDNA ratios that were significantly higher than those for ddI- and d4T+ddI-containing regimens (P<.01) but that were not significantly higher than those for d4T- or ZDV-containing regimens. Patients received thymidine analogue- and/or ddI-containing regimens for a shorter time (median, 14 vs. 24 months; P<.01). Because of survivor-bias effect, these results may represent a conservative estimate of these nucleosides' effect on mtDNA.