Aims and objectives To identify the prevalence and determinants of medication administration errors (MAEs). Background Insight into determinants of MAEs is necessary to identify interventions to prevent MAEs. Design A prospective observational study in two Dutch hospitals, a university and teaching hospital. Methods Data were collected by observation. The primary outcome was the proportion of administrations with one or more MAEs. Secondary outcomes were the type, severity and determinants of MAEs. Multivariable mixed‐effects logistic regression analyses were used for determinant analysis. Reporting adheres to the STROBE guideline. Results MAEs occurred in 352 of 2576 medication administrations (13.7%). Of all MAEs (n = 380), the most prevalent types were omission (n = 87) and wrong medication handling (n = 75). Forty‐five MAEs (11.8%) were potentially harmful. The pharmaceutical forms oral liquid (odds ratio [OR] 3.22, 95% confidence interval [CI] 1.43–7.25), infusion (OR 1.73, CI 1.02–2.94), injection (OR 3.52, CI 2.00–6.21), ointment (OR 10.78, CI 2.10–55.26), suppository/enema (OR 6.39, CI 1.13–36.03) and miscellaneous (OR 6.17, CI 1.90–20.04) were more prone to MAEs compared to oral solid. MAEs were more likely to occur when medication was administered between 10 a.m.–2 p.m. (OR 1.91, CI 1.06–3.46) and 6 p.m.–7 a.m. (OR 1.88, CI 1.00–3.52) compared to 7 a.m.–10 a.m. and when administered by staff with higher professional education compared to staff with secondary vocational education (OR 1.68, CI 1.03–2.74). MAEs were less likely to occur in the teaching hospital (OR 0.17, CI 0.08–0.33). Day of the week, patient‐to‐nurse ratio, interruptions and other nurse characteristics (degree, experience, employment type) were not associated with MAEs. Conclusions This study identified a high MAE prevalence. Identified determinants suggest that focusing interventions on complex pharmaceutical forms and error‐prone administration times may contribute to MAE reduction. Relevance to clinical practice The findings of this study can be used to develop targeted interventions to improve patient safety.