Resistance of Staphylococcus (S.) aureus to the currently used antimicrobials has risen dramatically in the past years creating a medical challenge as therapeutic options became very limited. This study aimed to screen and detect the prevalence of some antimicrobial-resistant genes of S. aureus clinical isolates recovered from patients suffering lower respiratory tract infections (LRTI) in Egypt. A total of 231 bacterial isolates were recovered from sputum and bronchoalveolar lavage specimens obtained from patients with LRTI. Thirty-seven isolates (16%) were identified as S. aureus where seventeen isolates (46%) showed resistance to ten or more antimicrobials. The antimicrobial susceptibility testing revealed that all the tested isolates were sensitive to vancomycin and linezolid (0%), however, the lowest resistance was observed to doxycycline (3%), and the highest resistance was observed to ciprofloxacin (51%). Sixteen isolates (43%) were found resistant to cefoxitin and harbored the mecA gene (100%). However, the mepA gene was detected in only 12 isolates (75%). Extended-spectrum β-lactamase (ESBL) including, ctx-m, shv and tem and the aac(6')-Ib genes, were detected in 10 (62%) and 8 (50%) isolates, respectively. None of the carbapenem-resistant genes including kpc, imp, vim, ndm, and oxa, were detected in any isolate. Multiple drug resistance (MDR) is a major health concern limiting the use of common antimicrobials in therapy. Thus, new national guidelines, as well as infection control strategies including antibiotic stewardship, must be implemented in the Egyptian hospitals to limit further spread of antimicrobial resistance.