Houttuynia cordata Thunb. fermentation product (HCFP) is widely used in Thailand as a dietary supplement for immune support with no experimental verification. The aim of this study was to investigate the safety and immunomodulation of HCFP in healthy adult volunteers. The effect of HCFP on antiretroviral drugs (TDF and EFV) was also evaluated in Sprague Dawley rats. The basic characteristics and blood chemistry of ten healthy volunteers did not show any significant differences between before and after 4 weeks of intervention with a daily intake of HCFP, and no major adverse event was observed. However, the LDL-c level was significantly decreased after 4 weeks of intervention. Immunomodulation assay revealed that the percentage of neutrophil was significantly increased after 8 weeks of intervention in 30 healthy volunteers. Meanwhile, the mean of CD4+ and CD8+ T-cell ratio was not significantly increased after 8 weeks of intervention. In addition, the plasma concentrations of EFV and TDF in Sprague Dawley rats showed no significant difference between single drug group and combination with HCFP group, suggesting that HCFP has no effect on the plasma level of antiretroviral drugs.