BACKGROUND: Acid-base homeostasis is increasingly being recognized to play an important role in normal metabolic function. However, prospective studies on the relationship between diet-induced acid-base imbalance and insulin resistance among Asian populations have been limited. Thus, we investigated whether diet-induced metabolic acidosis was prospectively associated with insulin resistance risk in middle-aged and older Korean adults. METHODS: In total, 5406 participants from the Korean Genome and Epidemiology Study without type 2 diabetes, insulin resistance, cancer, or renal diseases at baseline examination were included in this study. To estimate diet-induced metabolic acidosis, we used potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores calculated from the usual dietary intake assessed by a validated 103-item food frequency questionnaire at baseline. Multivariable Cox proportional hazard models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of insulin resistance incidence. RESULTS: During a mean follow-up period of 7.4 years, we documented 3449 insulin resistance cases. In the fully adjusted model, the future insulin resistance risk was significantly higher among participants in the highest quartiles of PRAL (HR: 1.30, 95% CI: 1.13-1.48, P = 0.0002) and NEAP (HR: 1.30, 95% CI: 1.14-1.49, P = 0.0008) than among those in the lowest quartiles. Associations were slightly strengthened among men, adults < 50 years old, obese participants, or those with low physical activity levels. CONCLUSIONS: Our findings suggested that diet-dependent acid load was positively associated with the future development of insulin resistance, suggesting effect modification by sex, age, the presence of obesity, and physical activity levels.