AimsThe aims of this study were to estimate potentially clinically important drug–drug interaction (DDI) prevalence, and the average causal effect of DDI exposure on adverse drug reaction (ADR)‐related hospital admission, and to examine differences in health‐related quality of life (HRQoL) and length of stay (LOS) per DDI exposure in an older (≥65 years) population acutely hospitalized.MethodsThis was a cross‐sectional study conducted among 798 older individuals acutely admitted to hospital in Ireland between 2016 and 2017. Medication (current/recently discontinued/over‐the‐counter) and clinical data (e.g., creatinine clearance) were available. DDIs were identified using the British National Formulary (BNF) and Stockley's Drug Interactions. Causal inference models for DDI exposure on ADR‐related hospital admission were developed using directed acyclic graphs. Multivariable logistic regression was used to estimate the average causal effect. Differences in HRQoL (EQ‐5D) and LOS per DDI exposure were examined non‐parametrically. DDI prevalence, adjusted odds ratios (aOR), and 95% confidence intervals (CIs) are reported.ResultsA total of 782 (98.0%) individuals using two or more drugs were included. Mean age was 80.9 (SD ± 7.5) years (range: 66–105); 52.2% were female; and 45.1% (n = 353) had an ADR‐related admission. At admission, 316 (40.4% [95% CI: 37.0–43.9]) patients had at least one DDI. The average causal effect of DDI exposure on ADR‐related hospital admission was aOR = 1.21 [95% CI: 0.89–1.64]. This was significantly increased by exposure to: DDIs which increase bleeding risk (aOR = 2.00 [1.26–3.12]); aspirin‐warfarin (aOR = 2.78 [1.37–5.65]); and esomeprazole‐escitalopram (aOR = 3.22 [1.13–10.25]. DDI‐exposed patients had lower HRQoL (mean EQ‐5D = 0.49 [±0.39]) compared those non‐DDI‐exposed (mean EQ‐5D = 0.57 [±0.41]), (P = .03); and greater median LOS in hospital (8 [IQR5–16]days) compared those non‐DDI‐exposed (7 [IQR 4–14] days),(P = .04).ConclusionsPotentially clinically important DDIs carry an increased average causal effect on ADR‐related admission, significantly (two‐fold) by exposure to DDIs that increase bleeding risk, which should be targeted for medicine optimization.