In spite of the growing attention to the combined chemotherapy in the treatment of AIDS, the molecular mechanisms underlying the antiviral synergy of combinations of reverse transcriptase (RT) inhibitors are in most cases unknown. Most combinations of nonnucleoside inhibitors (NNRTI) with nucleoside analogues synergistically inhibit HIV-1 replication in cell culture, though they fail to show synergy in enzymatic assays. In this work we have examined the mechanisms mediating the synergy in combinations of AZTTP with NNRTIs on HIV-1 RT and their possible relevance in antiretroviral therapy. We found that if two inhibitors bind either to different sites on the RT or to the same site but to different mechanistic forms, it is always possible to find conditions in which their combination results in synergistic inhibition of DNA polymerase activity. Though these analyses are interesting from a biochemical point of view, this kind of synergy is unlikely to play any role in vivo, since this positive interaction is lost under the conditions present in viral replication. Here we describe that the synergy found for combinations of NNRTI with AZT is due not to the inhibition of the DNA polymerase activity but to the inhibition of the RT-catalyzed phosphorolysis by the NNRTI. While phosphorolytical removal of the AZT-terminated primer has been related to the mechanism of resistance toward AZT, our data suggest that a basal phosphorolysis occurs even with the wild-type enzyme, and that the inhibition of this activity could explain the synergy found in antiviral assays.