Objectives: Interruptions occur frequently in the intensive care unit (ICU) and are associated with errors. To date, no causal connection has been established between interruptions and errors in healthcare. It is important to know whether interruptions directly cause errors before implementing interventions designed to reduce interruptions in ICUs. The aim of the study was to investigate whether ICU nurses who receive a higher number of workplace interruptions commit more clinical errors and procedural failures than those who receive a lower number of interruptions. Methods: We conducted a prospective controlled trial in a high-fidelity ICU simulator. A volunteer sample of ICU nurses from a single unit prepared and administered intravenous medications for a patient manikin. Nurses received either 3 (n = 35) or 12 (n = 35) scenario-relevant interruptions and were allocated to either condition in an alternating fashion. Primary outcomes were the number of clinical errors and procedural failures committed by each nurse. Results: The rate ratio of clinical errors committed by nurses who received 12 interruptions compared with nurses who received 3 interruptions was 2.0 (95% confidence interval = 1.41–2.83, P < 0.001). The rate ratio of procedural failures committed by nurses who received 12 interruptions compared with nurses who were interrupted 3 times was 1.2 (95% confidence interval = 1.05–1.37, P = 0.006). Conclusions: More workplace interruptions during medication preparation and administration lead to more clinical errors and procedural failures. Reducing the frequency of interruptions may reduce the number of errors committed; however, this should be balanced against important information that interruptions communicate.