Four novel sulfonic acid polymers were evaluated for their in vitro HIV-1 and HIV-2 reverse transcriptase (RT) inhibitory activity and found to be equipotent against both RTs. The aromatic polymers demonstrated IC50 values that were approximately 10(3)-fold lower than those observed with the aliphatic polymers. Among the aromatic polymers, poly(4-styrenesulfonic acid) (PSS) (MW 8000; IC50 = 0.02 microgram/ml) was 3-fold more potent than poly(anetholesulfonic acid) (PAS) of approximately the same molecular weight range. The activity of PSS polymers increased in proportion to the size of the polymers and, relative to suramin, activity could be enhanced over 200-fold. These polymers also inhibited the cytopathic effect of HIV-1 at concentrations that were non-toxic to MT-4 cells. The potent RT inhibitory properties of these stable sulfonic acid polymers suggest that structure-activity studies are warranted to yield agents capable of inhibiting multiple stages of the viral process.