Nurse calls in a hospital can constitute either positive or negative (wanted or unwanted) interruptions depending on various factors. This study aims to understand nurses’ strategies in facilitating the reception of wanted nurse calls and the restriction of unwanted nurse calls. Applying a resilience engineering perspective, nurses’ performance variability is investigated as a basis to design appropriate computer support to enhance efficiency and patient safety. A qualitative case study was conducted for a period of 4 years with focus on nurses’ use of a wireless nurse call system at a Norwegian university hospital. The study involved various data collection methods such as observations, interviews, and workshops. The collected data were then transcribed and analyzed using a combined inductive and deductive approach. Results indicate that nurses use four main strategies involving a large degree of collaboration to allow or avoid interruptions in the form of nurse calls depending on situation and circumstances. However, these strategies are not supported by the wireless nurse call system, which requires nurses to use suboptimal workarounds to enable the necessary performance variability. Interruptions have been largely perceived as a threat to patient safety. However, nurses’ handling of calls illustrates that, when aiming to introduce interventions to manage interruptions, a detailed understanding of work as done is important. Nurses continuously make appropriate adjustments to cope with challenges that characterize hospital work to ensure efficient and safe operations. Hence, technology, in terms of a nurse call system, needs to be designed to afford the adjustments made to support a resilient practice and, as such, leverage patient safety.