We analyzed the reverse transcriptase (RT) and protease sequences of HIV-1 isolates obtained over 7 years from two couples with known transmission histories. Phylogenetic trees constructed from the sequence data reflected the known transmission histories, despite the fact that the drug resistance mutations were most consistent with the drug treatment histories. However, the RT sequences from one couple diverged by 2.9% even before therapy was begun, and three (0.9%) of 339 unrelated individuals had viruses that shared a common ancestor with sequences from the recipient member of the couple but not with sequences from the transmitter. The divergence between the first two isolates from this couple is consistent with a pretransmission interval during which the transmitter developed a heterogeneous virus population. The closeness between the three controls and the recipient's first RT sequence may indicate slower evolution on the branches of the control sequences. Although the RT and protease genes contain phylogenetic information, they are suboptimal for reconstructing transmission history because the genetic distance between RT and protease isolates from unrelated individuals may occasionally approximate the distance between RT and protease isolates from related individuals.