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Background: The emergence of Penicillin resistance and multidrug-resistant pneumococcal strains is a global concern. Several reports have demonstrated a correlation between increased Minimal Inhibitory Concentration (MIC) of Penicillin, and increased MICs of Cephalosporins and other β-lactam antibiotics. It should be pointed out that pneumococcal resistance to Penicillin may predict an unfavorable response to other β-lactam antibiotics. Objectives: To outline pneumococcal resistance to Ceftriaxone, a microbiological survey was performed on pneumococcal strains, during a two-year period. Patients and Methods: In this study, 35 strains of Pneumococci were isolated from blood samples of 35 different consecutive patients, admitted to two educational hospitals in Mashhad, North East of Iran during a two-year period of this prospective study, the minimal inhibitory concentration (MIC) of Ceftriaxone was determined, using E-test. Results: Amongst 35 clinical isolates, evaluated in this study, only one isolate (2.86%) was resistant to Ceftriaxone (MIC > 1) and 34 isolates (97.14%) appeared to be sensitive to this antibiotic. MIC ranged from 0.012 to 6 and MIC50 and MIC90 were 0.07 and 0.5, respectively. Conclusions: Considering the low rate of Ceftriaxone resistance amongst isolated pneumcocci.in this study, Only Ceftriaxone treatment of adult patients with invasive pneumococcal infections (other than CNS infections) is sufficient; but pediatric patients and patients with CNS infections should be treated with Ceftriaxone and Vancomycin. Apparently, diminution of Vancomycin use can be resulted in reduction of the resistance rate among other bacteria, sensitive to this antimicrobial agent, such as Methicillin-resistant Staphylococcus aureus and Enterococci.