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Digoxin is an important medication for heart failure (HF) patients and sennosides are widely used to treat constipation. Recently, safety concerns have been raised about a possible interaction between sennosides and digoxin, an issue that has not been studied empirically. This study therefore aimed to evaluate whether exposure to sennoside–digoxin interaction is associated with an increased risk of digoxin toxicity.This was a population-based nested case–control study that analysed data obtained from the Taiwan National Health Insurance Research Database between 1 January 2001 and 31 December 2004. All HF patients treated with digoxin for the first time were included as the study cohort. Of these, cases were identified as subjects hospitalized for digoxin toxicity (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM 972.1), and matched to randomly selected controls. Use of sennosides was compared between the two groups. Odds ratios (ORs) were employed to quantify the risk associated with exposure to sennoside–digoxin interaction by conditional logistic regression. The study cohort comprised 222 527 HF patients, of whom 524 were identified as cases and 2 502 as matched controls. Use of sennosides during the 14 days preceding the index date was found to be associated with a 1.61-fold increased risk of digoxin toxicity [95% confidence interval (CI) = 1.15, 2.25]. Additionally, a greater risk was observed for sennosides prescribed at an average daily dose ≥24 mg (adjusted OR = 1.93; 95% CI = 1.27, 2.94).The combined use of sennosides and digoxin was found to be associated with a modest increased risk of digoxin toxicity in HF patients.