Although chronic pancreatitis is a known predictor of type 2 diabetes mellitus (T2DM), no previous studies have determined whether serum amylase (AMY) could be a predictor of T2DM with consideration of fasting plasma glucose (FPG) and HbA1c. We analyzed a historical cohort of 2,238 individuals without T2DM who underwent health examinations on an annual basis with a mean follow-up period of 9.6 y. AMY was categorized into quartiles and a multivariate Cox model was used to estimate the hazard ratio for incident T2DM. During a 10-y follow-up, 228 individuals developed T2DM. Median and interquartile range of baseline AMY(IU/L) was 74(62-91). Baseline AMY was significantly lower for participants who developed T2D compared to those who did not (71(59-84) vs. 75(62-92), p <0.001). When participants were stratified by age group (≤ 40 y, 41-50 y, 51-60 y, ≥ 61 y), AMY significantly increased with age among those who did not develop T2DM (p for trend <0.001), whereas there was no such significant trend among those who developed T2DM (p for trend = 0.18). After multivariate adjustment, lower AMY was associated with increased risk of T2DM independently of HbA1c (Q4, ref.; Q3, 1.21(0.78-1.90); Q2, 1.91(1.23-2.97); Q1, 1.61(1.01-2.56), p for trend = 0.01), but the association was not significant when adjusted for FPG (Q4, ref.; Q3, 1.10(0.66-1.61); Q2, 1.42(0.92-2.21); Q1, 1.23(0.78-1.93), p for trend = 0.21). The significantly increased risk for T2DM according to lower AMY quartiles even after multivariate adjustment including HbA1c (Q4, ref; Q3, 1.71(0.65-4.54); Q2, 3.30(1.17-9.23); Q1, 5.21(1.91-14.20), p for trend <0.001) was only found among those age ≥60 y.These results implied that low AMY is an independent predictor of T2DM especially among older people. Reasons for differences in effects of adjustment for HbA1c and FPG are unknown but are speculated to be associated with basal rather than postprandial glucose/insulin levels. Disclosure D. Ishii: None. K. Fujihara: None. M. Harada: None. M. Ishizawa: None. S. Kodama: None. K. Saito: None. Y. Mori: None. R. Yamamoto-Honda: None. Y. Arase: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..