No effective treatment for TSP/HAM has been described so far. Interventions with corticosteroids, plasmapheresis, interferon and, more recently, with antiretroviral drugs have been tried with poor results. The main HTLV replication mechanism is thought to be through clonal expansion of HTLV-infected cells, which excludes the involvement of the reverse transcriptase (RT) enzyme. However, a virological and clinical improvement has been noticed in HTLV-I carriers suffering from TSP/HAM receiving zidovudine or lamivudine. Herein, we describe the virological and clinical outcome in two TSP/HAM patients infected with HTLV-I treated with zidovudine plus lamivudine, and in two HTLV-II/HIV-1 co-infected patients receiving triple combinations including lamivudine. While, one TSP/HAM patient experienced a 2 log decrease in HTLV-I proviral load, an increase of 1 log was observed in another patient after several months of treatment with zidovudine plus lamivudine. The two HTLV-II/HIV-1 co-infected patients showed an initial increase in HTLV-II proviral load after beginning HAART followed by a slight decline a few months later. Plasma HIV-1 RNA fell to <50 copies/ml in both patients after beginning therapy. None of the four HTLV positive patients developed genetic changes at the conserved YMDD domain within their respective RT genes, which could be related to lamivudine resistance. No clinical improvement was observed in one TSP/HAM patient after more than 1 year on treatment with nucleoside analogues. The inhibition of the HTLV RT along with the cytostatic effect of some nucleoside analogues, including zidovudine, could reduce HTLV replication, and therefore reduce HTLV proviral load. The clinical consequences of this effect need to be further examined.