OBJECTIVES: To evaluate whether the interaction between diuretics and digoxin increases the risk of subsequent hospitalization for digoxin intoxication. METHODS: This study was a retrospective claims database analysis with a population-based nested case-control study design. Data for this study were extracted from the National Health Insurance Research Database between January 1, 2000 and December 31, 2004. A study cohort was identified as all CHF patients with continuous digoxin use. Cases were then identified as those with hospitalization for digoxin intoxication (ICD-9-CM 972.1), and the hospitalization dates were defined as the index dates. Each case was matched to randomly select with up to 50 controls by age, sex, date of cohort entry, and occurrence of chronic kidney disease, and the selected controls were assigned the index date of the corresponding case. Use of diuretics including thiazide diuretics, loop diuretics, and potassium-sparing diuretics was evaluated during the one month period before the index date for cases and controls. Conditional multiple logistic regressions were employed to model the association. RESULTS: A total of CHF127,101 patients continuously treated with digoxin was eligible to be the study cohort, from which 505 cases and 24,279 matched controls were identified. Patients with digoxin intoxication were 2.6 times (adjusted OR = 2.6; 95% CI = 2.1, 3.3) more likely to be prescribed to any diuretics in the previous month compared to controls. When diuretics were categorized into the three types, loop diuretics were associated with the most increased risk of hospitalization for digoxin intoxication (adjusted OR = 2.1; 95% CI = 1.7, 2.5), followed by potassium-sparing diuretics (adjusted OR = 1.5; 95% CI = 1.2, 1.9) and thiazide diuretics (adjusted OR = 1.4; 95% CI = 1.1, 1.8). CONCLUSIONS: The combined use of diuretics and digoxin was associated with an increased risk of hospital admissions for digoxin intoxication among CHF patients.