The antiviral effects of selected combinations between acemannan (ACE-M), a long-chained, polydispersed, beta-(1,4)-acetylated mannan, were tested in combination with azidothymidine (AZT) and acyclovir (ACY) in vitro. The rationale for such combinations was based on the antiviral and immunomodulatory properties exhibited by ACE-M. In addition, the observed antiviral effects of ACE-M against human immunodeficiency virus type 1 (HIV-1) and other enveloped viruses appear to be related to modification of the glycosylation of viral glycoproteins. Therefore, the inhibitory effect of ACE-M does not overlap with that of AZT or ACY. The studies presented herein show that ACE-M combined with suboptimal noncytotoxic concentrations of AZT or ACY act synergistically to inhibit the replication of HIV-1 and herpes simplex virus type 1 (HSV-1), respectively. The median effect method was not applicable for analysis because the test compounds show mutually nonexclusive drug effects. For a meaningful evaluation and interpretation of the effects of drug combinations, the biological significance of combinations must be considered, that is, the protective effect of the combination, the noncytotoxicity of the combination, the mechanism(s) of action of the individual compounds comprising the combination, and so forth. With respect to effects on U1 cells latently infected with HIV-1, treatment with combinations of AZT and ACE-M does not potentiate virus replication.