Human-robot interaction (HRI) promises to be a means whereby manufacturing companies will be able to address current challenges like a higher demand for customization. However, despite comparably low costs, there are only few applications in practice. To date, it remains unclear which factors facilitate or hinder the successful introduction of industrial collaborative robots (cobots). In a three-step approach, we first developed a comprehensive two-dimensional framework covering three separate phases and four essential components for human-robot working systems. Secondly, we reviewed related literature to identify relevant success factors. Thirdly, in an online survey we asked leading representatives of German manufacturing companies (n = 81) to assess the importance of these factors from a practical point of view. The results reveal that besides technology-related factors like occupational safety and appropriate cobot configuration, employee-centered factors like the fear of job loss and ensuring an appropriate level of trust in the robot are considered important. However, company representatives seem to underestimate the impact of subtle measures to increase employee acceptance which could be incorporated into internal communication strategies prior to and during the introduction of cobots. Comparative analysis based on three distinct application scenarios suggests that most success factors’ practical importance is independent of the motivation for implementing HRI. Furthermore, answers from practitioners in free-text fields reveal that success factors which intuitively come to their mind such as financial factors are not necessarily perceived most important. Finally, we argue for more application-oriented research that focuses on practically relevant factors to guide HRI research, inform cobot development, and support companies in overcoming apparent barriers.