The effect of glycyrrhizin (GR) on HIV replication in cultures of peripheral blood mononuclear cells (PBMC) from HIV-infected patients was investigated. After the depletion of CD8+ T cells, PBMC from HIV+ patients (patient PBMC) and PBMC from healthy donors (healthy PBMC) were cocultured in the presence or absence of GR (100 µg/ml) for 21 days. In cultures of 13 of 42 samples of patient PBMC (13/42, 31%), GR inhibited more than 90% of HIV replication. Among 42 samples of patient PBMC, 20 were identified to be infected with a non-syncytium-inducing variant of HIV (NSI-HIV), 15 with a syncytium-inducing variant of HIV (SI-HIV), and the remaining 7 were classified as cells infected with SI-HIV and/or NSI-HIV. GR inhibited more than 90% of HIV replication in cultures of 12 patient PBMC samples infected with NSI-HIV (12/20, 60%). In patient PBMC infected with SI-HIV, GR inhibited HIV replication in only 1 patient (1/15, 7%). In cultures of patient PBMC, GR induced the production of CC chemokine ligand (CCL)4 and CCL5 in a dose-dependent manner. When the assay was performed in PBMC cultures supplemented with a mixture of monoclonal antibodies for CCL4 and CCL5, no evidence of anti-HIV activity of GR was found. These results indicate that GR has the potential to inhibit NSI-HIV replication in patient PBMC cultures by inducing the production of β-chemokines.