Background: Group A streptococci (GAS) is a major cause of morbidity and mortality. Erythromycin is an effective macrolide antibiotic for treating GAS infections. However, GAS macrolide resistance has been increased due to either an efflux mechanism (M phenotype), encoded by mef A gene, or by methylation of the ribosomal target resulting in resistance to macrolide, lincosamide, and streptogramin B (MLS) antibiotics. Methylase can be expressed either constitutively (cMLS phenotype) or inducibly (iMLS phenotype). Objectives: The present study aimed to find out frequency of S. pyogenes isolated from patients with upper respiratory tract infections at Beni-Suef University Hospital, determine rate and mechanism of macrolide resistance. Methodology: The present study was conducted on patients with upper respiratory tract infections attended to otorhinolaryngology clinic, Beni-Suef University Hospital, Egypt, in the period from February to December 2015. Detailed history taking was carried and clinical findings were obtained. Throat or ear swabs were taken and processed by conventional bacteriological methods. S. pyogenes isolates were further tested to determine erythromycin resistance phenotype by D- test, MIC of Erythromycin by tube broth dilution method and for mef A gene by PCR. Results: Forty two S. pyogenes isolates were identified from (100) swabs taken from either ear or throat specimens (42%), isolates resistance to erythromycin and clindamycin was 83.3% (35) and 31% (13) respectively. The pattern of macrolide resistance was 31% (13/ 42) cMLS phenotype, 52.3% (22/42) M phenotype and no isolate was iMLSB phenotype. Most strains with M phenotype expressed low-level macrolide resistance (MIC 1-4μg/ml), while cMLSB isolates showed a high level of erythromycin resistance (MIC ≥64 μg/ml) (highly significant: p-value 0.0001). The results confirmed a strong correlation between the M phenotype and the mef A gene in GAS (highly significant: p-value =0.001). Conclusion: Incidence of erythromycin resistance was evident among the isolates. To preserve the necessary efficacy, limited use of erythromycin is recommended.