Piptoporus betulinus, the mushroom that has been carried by Ötzi the "Iceman", has a long tradition of use in medicinal practice for its antiseptic, anticancer, and immune-enhancing properties. With this study, we aimed to investigate the immunomodulatory effects of P. betulinus on primary human immunocompetent cells. The influence of P. betulinus water and methanol extract on apoptosis and necrosis induction of T cells and monocytes was analyzed using annexin V/propidium iodide staining and proliferation of T cells by carboxyfluorescein diacetate succinimidyl ester staining using flow cytometry. The effects on T-cell activation (CD69/CD25) and dendritic cell maturation (CD83, CD86, and CD14) were assessed using flow cytometric analysis of distinct marker expression. Alterations of the secretion of effector mediators interferon (IFN)-γ by T cells and interleukin (IL)-8 by monocytes and dendritic cells were detected by enzyme-linked immunosorbent assay. None of the P. betulinus extracts had a significant influence on apoptosis and necrosis induction, T-cell proliferation, or T-cell activation status, but P. betulinus water extract caused a strong increase in IFN-γ release. The same extract was slightly protective against apoptosis of monocytes and further triggered IL-8 secretion by monocytes and dendritic cells. Moreover, P. betulinus water extract induced dendritic cell maturation. Our results demonstrate the immune-enhancing properties of P. betulinus.