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Background: Streptococcus pyogenes most commonly cause pharyngitis, also has been associated with invasive infection as sepsis & fulminate systemic infections . It is imperative cause for fatal condition in children like acute rheumatic fever & rheumatic heart disease. Development of strains that resistant to antibiotics makes such disease a dangerous clinical challenge particularly in children, so in order to overcomingthis resistance, a nonsteroidal anti-inflammatory drugs (NSAID) is repurposed as antimicrobials against this microorganisms to be combined with the anti-microbial suggested by WHO rule of care.Aims: To evaluate the antimicrobial activity of aspirin & an aspirin-cefixime combination against multidrugresistant S.pyogenes isolated from clinical cases of pharyngitis.Materials, Patients and Methods: S.pyogenes,a multidrug-resistant strain, was isolated from patients had pharyngitis. It was cultivated for determination of MIC for aspirin-cefixime combination in relationship with each drug alone &to determine combination index.Results and Conclusions: a significant synergism was found between aspirin-cefixime ( combination index ˂ 1) P= 0.009& Z score= 2.5 further confirmation of MIC had assessed bytwo folds of dilutions to achieve reasonable evidence. Conclusion:There was a significant synergistic effect achieved from combining aspirin with cefixime against S.pyogenes isolate in culture . Recommendations:We recommended further evaluation for the antistreptococcal effect of the combined aspirin-cefixime on more dilutions of MIC assay & to investigate data of this combination clinically in patients with S.pyogenes pharyngitis.