Background As hospitals are under increasing pressure to improve quality and safety, safety culture has become a focal issue for high-risk organizations, including hospitals. Prior research has examined how structural characteristics directly impact safety culture. However, and based on Donabedian's structure-process-outcome quality model, there is a need to understand the processes that intermediate the relationship between structural characteristics and safety culture perceptions. Purpose The processes by which registered nurse (RN) and hospitalist staffing may affect safety culture perceptions were examined in this study. Specifically, this study investigates the processes of perceived teamwork across units and perceived handoffs. Methodology Data sources for this research included Hospital Survey on Patient Safety Culture from the Agency for Healthcare Research and Quality, the American Hospital Association's Annual Survey Data, the American Hospital Association Information Technology supplement, and the Area Health Resource File. Two separate mediation models for each process were used. Propensity weights were assigned to each hospital in the sample (N = 207) to adjust for potential nonresponse bias of hospitals that did not assess employee's safety culture perceptions. Results Results suggest that RN staffing influences safety culture perceptions, but hospitalist staffing does not. In addition, RN staffing has an indirect effect on safety culture perceptions through better processes. Practice Implications Our study sheds light on how staffing affects safety culture perceptions. Specifically, our findings suggest that positive perceptions of teamwork across units and handoffs are integral in the relationship between RN staffing and safety culture perceptions. Hospital managers should, therefore, invest resources in staff recruitment and retention. In addition, a targeted focus on perceived teamwork and handoffs may allow hospital managers to improve safety culture perceptions.