Prolonged and exhausting physical activity causes numerous changes in immunity and sometimes transient increases the risk of upper respiratory tract infections (URTIs). Nutritional supplements as countermeasures to exercise-induced changes have increasingly been studied in the last decade. One of the most promising nutritional supplements is β-glucan, a well-known immunomodulator with positive effects on the function of immunocompetent cells. In this double blind, placebo-controlled study, we investigated the effect of pleuran, an insoluble β-(1,3/1,6) glucan from mushroom Pleurotus ostreatus, on selected cellular immune responses and incidence of URTI symptoms in athletes. Fifty athletes were randomized to pleuran or placebo group, taking pleuran (commercial name Imunoglukan(®)) or placebo supplements during 3 months. Venous whole blood was collected before and after 3 months of supplementation and additionally 3 months after supplementation period was completed. Incidence of URTI symptoms together with characterization of changes in phagocytosis and natural killer (NK) cell count was monitored during the study. We found that pleuran significantly reduced the incidence of URTI symptoms and increased the number of circulating NK cells. In addition, the phagocytosis process remained stable in pleuran group during the study in contrast to placebo group where significant reduction of phagocytosis was observed. These findings indicate that pleuran may serve as an effective nutritional supplement for athletes under heavy physical training. Additional research is needed to determine the mechanisms of pleuran function.