Background: Patient safety has been one of the basic tenets of medicine and healthcare since the time of Hippocrates. The data regarding patient safety awareness among health care workers in southwestern Saudi Arabia is scarce. Aim: To explore physicians and nurses' overall attitudes and perceptions towards patient safety culture and to evaluate any differences in their cultures. Methodology: This cross-sectional study of a representative sample of physicians and nurses working in a tertiary hospital was conducted using a self-administered questionnaire developed by the Agency for Healthcare Research and Quality. Results: The study included 369 participants. Their ages ranged from 18 to 60 years, with a mean age of 28.9 +/- 8.5 years. The majority of participants were females (70.7%). The mean score for the overall patient safety grade was 72.3. The highest rated patient safety dimensions (scores over 70%) were "teamwork within units", "organizational learning-continuous improvement" and "feedback and communication about errors". On the other hand, the lowest dimensions (scores less than 50%) were "non-punitive responses to errors" and "Staffing". A statistically significant difference between physicians and nurses were found in 8 dimensions out of 12 dimensions of patient safety culture. The overall scores of the unit-level safety culture were significantly higher among nurses than among physicians (65.9% and 63.6%, respectively, P=0.022). Similarly, in thehospital-level safetyculture, nurses had significantly higher safety culture scores than physicians (68.1% and 58.4%, respectively, P=0.001). Conclusions: Nurses and physicians scored patient safety differently. Their perceptions regarding "teamwork within units", "organizational learning-continuous improvement" and "feedback and communication" were good. However, other patient safety dimensions need to be improved. Overall, nurses' perceptions are significantly better than physicians' perceptions. To improve healthcare delivery in the region, capacity-building programs should focus on improving the patient safety culture among health care providers, in general and with physicians in particular. Further studies are recommended among healthcare workers at other levels of healthcare in the region in order to improve patient safety practices.