The availability of enfuvirtide enables assessment of whether human immunodeficiency virus (HIV) decay can be enhanced by targeting reverse transcriptase, protease, and fusion. We performed a 12-week study of 22 patients randomized to receive ritonavir-boosted saquinavir and efavirenz with (the 3- target arm) or without (the 2-target arm) enfuvirtide. We observed no difference in the mean_SD elimination-rate constant for overall decay (0.142±0.040 per day and 0.128 ±0.033 per day in the 2- and 3-target arms, respectively; P 1 .1) or for modeled first-phase decay rate (-0.62±0.34 per day and -0.51±0.16 per day; P 1 .1). Antiretroviral therapy that inhibits HIV reverse transcriptase and protease exerts potent antiviral effects that might not be augmented by the addition of an HIV fusion inhibitor.