β-glucan is widely distributed in nature as water soluble and insoluble forms. Both forms of β-glucan are applied in several fields, especially for functional foods. Yeast β-glucan is a medically important insoluble particle. Solubilization of yeast β-glucan may be a valuable approach to increase functional foods and medicinal fields. We have applied a heat degradation method to solubilize yeast β-glucan and found that it was effectively solubilized by treatment with an aqueous suspension at 135°C for several hours. The solubilized yeast β-glucan (hd-sBBG) exhibited antagonistic activity to the reactive oxygen production of macrophages and to the cytokine synthesis of macrophages. hd-sBBG strongly reacted with the anti-β-glucan antibody in human sera and with dectin-1, the innate immune receptor of β-glucan. From these findings, the heat degradation method is an important procedure for making immune modulating soluble yeast β-glucan.