Background: Multidrugs resistance is an emerging health problem that ultimately will lead to vanishing of effective medicine against infections including Staphylococcus epidermidis infections. Aim: This a prospective hospital base study of 58 Staphylococcus epidermidis clinical isolates in Assir region aim at evaluating the sensitivity profile of commonly used antibiotic during the period of March 2011- Sep. 2011. Materials and Methods: Bacteriology procedures ; staining, culture, catalase, coagulase and antibiotics sensitivity test using diffusion disc test, minimum inhibitory concentration (MIC) and molecular (PCR) for confirmation of Staphylococcal species and detection of the Mec A gene. Clinical and laboratory data were recorded in special formats and analyzed by statistical computer program (SPSS). Result: 58 Staphylococcus epidermidis clinical isolates including 14 diabetics. Age groups include 29 (0-15yrs), 14 (16-50yrs) and 15 (50yrs& above). The total resistance cases to Oxacillin/ Mithicillin was found to be 56 cases (96.4%); all non diabetics were resistance. Resistance and sensitivity to Ciprofloxacin among diabetic and non diabetic were 75.9% and 24.1% respectively. Total resistance to Fusidin were 81%, while total resistant to Erythromycin in all ages groups were 86.2%. In age group (0-15) years 93.1% were resistant to the drug which comprises, 54%of the total resistant cases (n=50) and 46.6% from all Staphylococcus epidermidis cases (n=58). Conclusion: Staphylococcus epidermidis is a pathogen associated with community acquired and nosocomial infections. The nosocomial infections are predominant in neonatal intensive care units (NICU). Resistance of Erythromycin in S. epidermidis cases among children is highly observed as this drug is commonly used by this age group. Diabetes has equivocal effect on drugs sensitivity. The frequency of staphylococcus multi-drugs resistance is rising.