There are several data in the literature indicating a great variety of pharmacological activities ofPolypodium genus, which exhibit antiinflammatory and immunomodulatory activities. Since oneof our main interests is to obtain natural immunoregulatory agents devoid of pharmacologicaladverse effects, we used flow cytometry analysis to highlight relative contributions of a water-soluble fraction of different concentrations of Polypodium rhizome extracts on lymphocytesubpopulations, NK and LAK activity. To measure their potential immunoregulatory activity a Tcell proliferation assay in response to phytohemaglutinin (PHA) and mixed lymphocyte reactionswere chosen. As a confirmatory bioassay we studied the effect of our extracts on CD45RO andCD95 antigen expressions. The results indicate that CD95 expression dramatically increases afterperipheral blood lymphocyte activation and treatment with Polypodium leucotomus, cambricum andvulgare extracts, suggesting a powerful intrinsic pro-apoptotic effect.