The thermodynamic treatment, which is based on the difference of heat of formation among three extreme cases for the substitution of a quaternary element X, was applied to predict the substitution behavior of quaternary elements in Ni3(Si,Ti). The heat of formation of a hypothetical ternary compound Ni6SiTi in which X elements substitute for relevant sites was calculated by using a geometric model based on an extended Miedema’s theory. According to the prediction, Cr and W (6), Mn and Re (7), Fe and Os (8), Co and Ir (9), Pt (10), and Cu and Au (11) substitute for Ni atoms. Ge (14) substitutes for Si atoms. Zr and Hf (4), V, Nb, and Ta (5), Mo (6), and Al (13) substitute for Ti atoms. Ga (13) substitutes for Si or Ti atom. The prediction for Ta is consistent with the reported experimental result. Also, the solubility limits of quaternary elements for the Ti site in Ni3(Si,Ti) are ranked in the sequence of Ta > Nb > V > Hf > Zr, and correlated with the size misfit parameter between Ti and the quaternary element X, and the difference in heats of formation between Ni6SiTi and Ni6SiX.