Fine-needle aspiration was used to collect lymph node cells (LNC) from 9 antiretroviral-naive patients entering a double-blind single- or combined-drug study of zidovudine, zalcitabine, and saquinavir. LNC were obtained twice before and 1 and 6 months after initiation of treatment. The effect of antiretroviral treatment on virus load ranged from no response to a dramatic decrease in plasma and LNC human immunodeficiency virus (HIV) RNA levels. The decrease in unspliced or spliced (or both) HIV RNAs in LNC was correlated with but consistently smaller than the decrease in plasma viremia. When present, the increase in blood CD4 T cells was, in general, moderate and transient. However, a striking rise in blood CD4 T cell count and in LNC CD4:CD8 ratio was observed in the 1 patient with the deepest sustained decrease in HIV RNA level in both plasma and lymph nodes.