The pH dependence of the reaction of human renin with sheep angiotensinogen had a couple of peaks at pH 6.5 and 8.7. The renin activity at pH 8.7 was 1.4 times higher than that at pH 6.5. After the substitutions of Phe, Ala, and His for Tyr83 of human renin, the peak at pH 6.5 could be observed but the peak at pH 8.7 disappeared. At pH 6.5, these substitutions reduced the kcat of human renin to 11.1, 1.31, and 3.49% of that of wild-type renin, respectively, while their Km remained at similar levels to that of the wild type. These results indicate that Tyr83 of human renin contributes to the renin-angiotensinogen reaction at both pHs and it is essential for the catalytic reaction particularly at the basic pH.