PURPOSE: This population-based, cross-sectional study was performed to assess the influence of life-style modalities, including physical activity, sedentary behaviors, and visual display terminal (VDT) use, on the prevalence of dry eye disease (DED). METHODS: The study included a total of 102,582 participants aged 40-74 years, from the Japan Public Health Center-based Prospective Study for the Next Generation, a large nationwide prospective ongoing Japanese cohort study. Logistic regression analyses were used to investigate the relationship of total and leisure-time physical activity, duration of sedentary behaviors, and VDT use (hours/day) with DED. RESULTS: Among 47,346 men and 55,236 women, 25,234 (8315 males and 16,919 females) cases of DED were documented. Total physical activity was significantly related to decreased DED in both sexes; for the highest vs. lowest total physical activity quartiles, the multivariable-adjusted odds ratios (ORs) for DED were 0.90 (95% confidence interval [CI], 0.84-0.97; Ptrend<0.03) and 0.91 (95% CI, 0.86-0.95; Ptrend<0.001) for men and women, respectively. Conversely, prolonged sedentary behaviors and VDT use had significantly higher prevalence of DED in both sexes (Ptrend<0.001). Notably, the favorable effect of total physical activity on decreased DED in women was more prevalent with prolonged VDT use (≥2 h/day) (Pinteraction<0.01). In men, the duration of VDT use or sitting was a significant modifier of the inverse relationship between leisure-time physical activity and DED (Pinteraction<0.05). CONCLUSIONS: Physical inactivity, prolonged sedentary behaviors, and use of VDT were related to increased susceptibility to DED among middle-aged to older Japanese adults.