The practice of cardiovascular surgery demands daily interface with sophisticated technologies including most commonly the cardiopulmonary bypass (CPB) machine. Although other industries have recognized the importance of considering human factors in the design of machines to reduce operator error, the evolution of the CPB machine over the past half-century has been characterized by incremental modifications of component parts with attention principally to mechanical efficiency and biocompatibility, but with little awareness of the impact of design changes on the human user. As a first step in the redesign of a safer pump, systematic observations of perfusionists during 10 adult and pediatric cases were conducted by staff cardiac surgeons and by human factors experts. Observations were classified according to accepted ergonomics principles. Perfusionists also performed usability evaluations and provided feedback concerning the design and functionality of bypass machines. Problems identified clustered around several usability themes. Issues with displays (8% of total comments) included location, legibility, format, and integration. Multiple problems with controls (11% of total comments) including location, sensitivity, and shape were identified, as were issues with audible alarms (6% of total comments). Component integration (14% of comments) and work-space design (21% of comments) were suboptimal as well. Procedural and communication issues (21% of comments) related to pump utilization, rather than pump design, were also identified, which stemmed from a lack of standardized operating room practices. Clinical issues (14% of comments) surrounding care of the patient were also identified but were not further analyzed, because these comments did not pertain to the design of the perfusion pump. Our observations confirmed the hypothesis that opportunities exist to incorporate usability and ergonomics insights into CPB machine design to optimize the human/technology interface. Such fundamental design considerations may improve the safety of the conduct of CPB and, consequently, outcomes after cardiovascular surgery.