Newly synthesized erythromycin derivatives were screened for synergy with oxacillin and other β-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA). MRSA ATCC43300 and some clinically isolated MRSA were used. Several erythromycin derivatives were found to possess high synergism with oxacillin against MRSA. The newly synthesized erythromycin derivatives were also tested for their inhibitory effects against MRSA, either separately or in combination with oxacillin, using serial broth dilution, disc diffusion, Etest strips, growth curves and time-kill curves. A representative derivative, SIPI-8294, could potentiate almost all β-lactam antibiotics tested against the model strain MRSA ATCC43300 from 4 to 128 times and had synergism with oxacillin against 12 of 16 clinical isolates of MRSA under one-fourth of the minimum inhibitory concentration (MIC) of the compounds. This is the first report on the synergistic activity of these new erythromycin derivatives. These findings provide a new choice for the treatment of infection caused by MRSA and lead us to further study the synergistic mechanism. Significance and Impact of the Study: This study is the first report on the synergy of anti-MRSA between new erythromycin derivatives and β-lactam antibiotics in vitro. The results show that although the erythromycin derivatives have poor anti-MRSA effects alone, they possess high synergism with oxacillin against MRSA ATCC43300 and clinically isolated MRSA. These novel compounds can significantly reduce the dosage of β-lactam antibiotics against MRSA, while this synergistic effect is different from the combination of β-lactams and β-lactamase inhibitors. The research may provide a new choice for the treatment of infection caused by MRSA and be useful to the research and development of new combination of medicines. Significance and Impact of the Study: This study is the first report on the synergy of anti-MRSA between new erythromycin derivatives and β-lactam antibiotics in vitro. The results show that although the erythromycin derivatives have poor anti-MRSA effects alone, they possess high synergism with oxacillin against MRSA ATCC43300 and clinically isolated MRSA. These novel compounds can significantly reduce the dosage of β-lactam antibiotics against MRSA, while this synergistic effect is different from the combination of β-lactams and β-lactamase inhibitors. The research may provide a new choice for the treatment of infection caused by MRSA and be useful to the research and development of new combination of medicines.