Plasma human immunodeficiency virus (HIV) type 1 RNA load is the reference marker for response to antiretroviral therapy. To compare peripheral blood mononuclear cell (PBMC)-associated and plasma HIV-1 RNA response to treatment, HIV-1 RNA was quantified by reverse transcription-competitive polymerase chain reaction in 20 patients at 0, 12, and 24 weeks following addition of saquinavir to their treatment regimens. HIV-1 RNA was undetectable in 15 plasma samples but in only 2 PBMC samples (P=.002) and CD4 cell counts correlated more with PBMC than with plasma HIV-1 RNA load. Changes in HIV-1 RNA load in PBMC and in plasma were correlated, and the decrease was higher in plasma than in PBMC at weeks 12 (P=.002) and 24 (P=.017). Moreover, PBMC, but not plasma HIV-1 load, at week 12 was predictive of HIV-1 RNA levels at week 24 in both plasma (P=.004) and PBMC (P<. 001). Thus, measurement of PBMC HIV-1 RNA may be useful during antiretroviral therapy.