Background. Methicillin-resistant Staphylococcus aureus (MRSA) is a well-recognized public health problem throughout the world. The evolution of new genetically distinct community-acquired and livestock-acquired MRSA and extended resistance to other non-β-lactams including vancomycin has only amplified the crisis. This paper presents data on the prevalence of MRSA and resistance pattern to other antibiotics on the selected specimen from two referral hospitals in Asmara, Eritrea. Method. A cross-sectional study was conducted among 130 participants recruited from two referral hospitals in Asmara, Eritrea. Isolation of S. aureus was based on culture and biochemical profiles. Standard antimicrobial disks representing multiple drug classes were subsequently set for oxacillin, gentamicin, erythromycin, and vancomycin. Data were analyzed using SPSS version 20 software. Results. S. aureus isolation rate from the 130 samples was 82 (63.1%). Patients <18 years of age were more likely to be colonized by S. aureus compared to patients above 61 years. The proportion of MRSA among the isolates was 59 (72%), methicillin-intermediate S. aureus (MISA) was 7 (8.5%), and methicillin-sensitive S. aureus (MSSA) was 15 (19.5%). The isolates were mostly from the pus specimen in burn, diabetic, and surgical wound patients. Antimicrobial susceptibility test showed that 13 (15.9%) of the isolates were resistant to vancomycin, 9 (11.0%) to erythromycin, and 1 (1.2%) to gentamicin. Coresistance of MRSA isolates to some commonly used antibiotics was also noted: oxacillin/erythromycin 5 (6.1%) and oxacillin/vancomycin 9 (11%). A few isolates were resistant to oxacillin/vancomycin/erythromycin 2 (2.4%) and oxacillin/gentamicin and erythromycin 1 (1.2%). Conclusion. This study reports a relatively high prevalence of MRSA. Isolates that are resistant to other tested antibiotics including vancomycin are also reported. The data have important implication for quality of patients care in the two settings: antibiotic selection and infection control practices, and the need for additional studies.