Despite the positive impact of information and communication technology (ICT) on an individual, organizational, and societal level (e.g., increased access to information, as well as enhanced performance and productivity), both scientific research and anecdotal evidence indicate that human-machine interaction, both in a private and organizational context, may lead to notable stress perceptions in users. This type of stress is referred to as technostress. A review of the literature shows that most studies used questionnaires to investigate the nature, antecedents, and consequences of technostress. Despite the value of the vast amount of questionnaire-based technostress research, we draw upon a different conceptual perspective, namely neurobiology. Specifically, we report on a laboratory experiment in which we investigated the effects of system breakdown on changes in users' levels of cortisol, which is a major stress hormone in humans. The results of our study show that cortisol levels increase significantly as a consequence of system breakdown in a human-computer interaction task. In demonstrating this effect, our study has major implications for ICT research, development, management, and health policy.We confirm the value of a category of research heretofore largely neglected in ICT-related disciplines (particularly in business and information systems engineering, BISE, as well as information systems research, ISR), and argue that future research investigating human-machine interactions should consider the neurobiological perspective as a valuable complement to traditional concepts.