Background and purpose: Uncomfortable care and histamine H2 antagonist (H2A) are implicated in precipitating delirium. In acute stroke, however, the need for them depends on stroke severity, an established risk factor for delirium. So, it is unclear whether care or H2A itself is responsible for delirium. We aimed to evaluate their causal effects on delirium in acute stroke patients. Methods: This is a prospective cohort study on acute stroke patients admitted to a stroke care unit. Patients without stupor, coma, sedation, or delirium upon admission were enrolled. The treatment was H2A and five care modalities given during the first 24 h: restraint use, prohibited self-transfer, no oral feeding, indwelling catheters, and frequent nighttime care. The outcome was delirium within 5 days defined as Intensive Care Delirium Screening Checklist ≥4 points. We estimated the relative risk (RR) for delirium with regression models weighted by overlap weights using propensity scores estimated through logistic models incorporating known and potential confounders, including stroke severity. Results: Of the 387 participants, 188 were given at least one care modality and 130 were given H2A. A total of 42 developed delirium. Delirium was significantly associated with prohibited self-transfer (RR 1.7, 95% CI 1.0-3.0), frequent nighttime care (RR 2.1, 95% CI 1.2-3.7), and multiple care modalities (RR 2.4, 95% CI 1.3-4.4), while other care modalities and H2A were not. Conclusions: This study showed possible causal effects of uncomfortable care on delirium and suggests that minimizing it could prevent delirium in acute stroke.