To assess the clarity and efficacy of the World Health Organization (WHO) hand-rub diagram, develop a modified version, and compare the 2 diagrams. Randomized group design preceded by controlled observation and iterative product redesigns. The Cognitive Ergonomics Lab in the School of Psychology at the Georgia Institute of Technology. We included participants who were unfamiliar with the WHO hand-rub diagram (convenience sampling) to ensure that performance was based on the diagram and not, for example, on prior experience. We iterated through the steps of a human factors design procedure: (1) Participants simulated hand hygiene using ultraviolet (UV) absorbent lotion and a hand-rub technique diagram (ie, WHO or a redesign). (2) Coverage, confusion judgments, and behavioral videos informed potentially improved diagrams. And (3) the redesigned diagrams were compared with the WHO version in a randomized group design. Coverage was assessed across 72 hand areas from multiple UV photographs. The WHO diagram led to multiple omissions in hand-surface coverage, including inadequate coverage by up to 75% of participants for the ulnar edge. The redesigns improved coverage significantly overall and often substantially. Human factors modification to the WHO diagram reduced inadequate coverage for naïve users. Implementation of an improved diagram should help in the prevention of healthcare-associated infections.