Objective: This study tested the ability of work relationships and work empowerment to predict nursing expertise in experienced acute care nurses. Background: With high patient acuity, constant system changes, and multiple changing members of the healthcare team, expert nurses are increasingly important to ensure positive patient outcomes in acute care settings. Method: This study was an exploratory, predictive correlational design with a stratified random sample of 115 staff nurses from a large tertiary care center. Data were collected on work empowerment, work relationships, and nursing expertise. Results: A modified study model was supported in this sample of acute care nurses (R2 = 0.258, P = .000) and explained 26% of nurses' reported expertise. Conclusion: Work relationships explained the largest portion of the variance in nurses' reported expertise (16%), more than experience in the specialty (9%) with an indirect link between work empowerment and nursing expertise.