Quantitative measurement of human immunodeficiency virus (HIV) RNA is being used to assess the efficacy of various treatment modalities in HIV disease. Topical dinitrochlorobenzene (DNCB) therapy has been associated with improved clinical and immunologic parameters in HIV-infected patients. We have now examined the effect of topical DNCB treatment on plasma HIV RNA levels in a small prospective study. Eight HIV-infected subjects had T-cell counts and plasma viral load measured prior to initiation of DNCB therapy and 3-4 months after starting treatment. Six patients who refused DNCB therapy served as simultaneous controls. The mean CD4 and CD8 T-cell counts did not change significantly in either group over the study period. In contrast, plasma HIV RNA levels decreased one-half to greater than one log in each DNCB-treated subject, and the decrease in viral copies was statistically significant (p = 0.006). In the control group, plasma HIV RNA levels increased significantly over the course of the study (p = 0.037). We conclude that topical DNCB therapy has the ability to lower viral load in HIV-infected patients. The long-term effect on viral burden of this inexpensive, readily available therapeutic modality merits further investigation.