HIV-1 RNA and DNA levels were measured in 58 patients, of whom 37 and 11, respectively, received triple or double combination therapy. At baseline, strong correlations were found between the number of HIV-1 DNA copies per 106 CD4+ cells, the plasma HIV-1 RNA levels, and the isolation rate of HIV-1 from blood cells. In comparison with HIV-1 RNA, a much slower decline in HIV-1 DNA levels was seen, which probably represents a long lifetime of provirus-bearing CD4+ cells. In 10 untreated patients, the proviral load was stable. In patients receiving triple therapy, a significant decline in HIV-1 DNA was seen independent of whether the proviral load was expressed as copies per 106 CD4+ cells or as copies per milliliter of blood. In contrast, a decline was seen only when the proviral load was expressed as copies per 10(6) CD4+ cells in patients given two drugs. The difference between the two patient categories is likely to be due to a more frequent infection of CD4+ cells during therapy in the patients with double therapy. Interpretation of changes in HIV-1 DNA levels is thus dependent on how the proviral burden is expressed. Further studies should evaluate whether changes in HIV-1 DNA load can be used as markers of viral replication during efficient antiretroviral combination therapy.