Abstract Context The interaction of glycated hemoglobin A1c (HbA1c) and glycemic variability in relation to diabetes-related outcomes remains unknown. Objective To evaluate the relationship between HbA1c and all-cause mortality across varying degrees of glycemic variability in patients with type 2 diabetes. Design, Setting, and Patients This was a prospective study conducted in a single referral center. Data of 6090 hospitalized patients with type 2 diabetes was analyzed. Glucose coefficient of variation [coefficient of variation (CV)] was obtained as the measure of glycemic variability by using continuous glucose monitoring for 3 days. Cox proportional hazards regression models were used to estimate hazard ratios and 95% CIs for all-cause mortality. Results During a median follow-up of 6.8 years, 815 patients died. In patients with the lowest and middle tertiles of glucose CV, HbA1c ≥ 8.0% was associated with 136% (95% CI 1.46-3.81) and 92% (95% CI 1.22-3.03) higher risks of all-cause mortality, respectively, as compared with HbA1c 6.0%-6.9%, after adjusting for confounders. However, a null association of HbA1c with mortality was found in patients with the highest tertile of glucose CV. Conclusions HbA1c may not be a robust marker of all-cause mortality in patients with high degree of glycemic variability. New metrics of glycemic control may be needed in these individuals to achieve better diabetes management.