Objective: To assess primary care physicians’ knowledge and practice related to diabetes mellitus in Aseer Region, Kingdom of Saudi Arabia (KSA). Subjects and Methods: A total of 153 primary health care (PHC) physicians were included from Aseer Region. Each participant physician was interviewed using a study questionnaire that comprised personal characteristics data sheet and PHC physicians’ assessment of knowledge (15 questions) and practices (10 questions). Results: Excellent knowledge and practice grades were attained by32.7% and 23.5%, respectively, while unsatisfactory knowledge and practice grades were attained by 8.5% and 22.2% of PHC physicians. PHC physicians who had significantly more “excellent” knowledge grades were older (p<0.001), non-Saudi (p<0.001), higher qualified (p=0.001), with more postgraduate experience (p<0.001), with better grades of practice (p<0.001), and those who attended courses on diabetes (p=0.006). PHC physicians who had significantly more “excellent” practice grades were older (p<0.001), non-Saudi (p=0.041), having Doctorate/Fellowship (p<0.001), having more years of postgraduate experience (p=0.001), seeing more diabetic patients (p<0.001), and those who attended courses on diabetes (p=0.008). Conclusions: PHC physicians’ knowledge and practice grades are suboptimal. Better knowledge and practice grades about diabetes are present among older, non-Saudi, higher qualified PHC physicians, with more postgraduate experience, better grades of practice, and those who attend courses on diabetes. Continuing medical education should be enforced for all PHC physicians, especially Saudi, younger, newly graduated PHC physicians.