Background: Previous studies evaluating work engagement of nurses revealed work-related factors and nurse demographics affecting work engagement. Low work engagement yields a decrease in productivity, high turnover, loss of revenue, and, most importantly, patient safety concerns. Aim: To investigate the relationship between nurse-related and work-related variables associated with work engagement and provide a model that explains work engagement. Method: This study employed an observational, cross-sectional study design, with 201 registered nurses working in acute care hospitals in the United States participating in the study. Four work-related and five nurse-related variables were evaluated and used in the work engagement model. A standard multiple regression was performed using the work-and nurse-related factors regressed onto work engagement. Structural equation model procedures were performed to examine the association between predictive variables and work engagement.