Combined beta-glucan with anti-tumor mAb therapy has demonstrated therapeutic efficacy in murine tumor models. The current study was designed to compare the therapeutic efficacy of various sources of beta-glucans. Our studies demonstrated that yeast beta-glucan, in combination with anti-tumor mAb, resulted in significantly smaller tumor burdens and achieved enhanced long-term survival compared to mAb alone or beta-glucan extracts from mushrooms. Further studies indicated that yeast beta-glucan particle was superior to mushroom extracts in inducing cytokine secretion, particularly IL-12 production in dendritic cells (DCs). In addition, results showed that cytokine production was markedly decreased in MyD88-deficient macrophages and DCs but not in complement receptor 3 (CR3)-deficient mice. Our data suggest that yeast beta-glucan demonstrates much stronger adjuvant activity compared to mushroom beta-glucan extracts in tumor therapy. This effect of yeast beta-glucan may be in part ascribed to the cytokine secretion by DCs and macrophages and bioavailability of active beta-glucan moiety.