A novel series of 4''-carbamates of 6,11-di-O-methylerythromycin A were synthesized and evaluated. These compounds have significant antibacterial activity against Gram-positive pathogens, including erythromycin-resistant but methicillin-susceptible Staphylococcus aureus, erythromycin-resistant and methicillin-resistant Staphylococcus aureus, erythromycin-resistant Streptococcus pneumoniae and Gram-negative pathogens, such as Haemophilus influenzae To our surprise, most of the derivatives tested had potent activity against most resistant bacteria. Among these, compounds 10u, 10v, 10w and 10y were found to have potent activity against most susceptible and resistant bacteria. In particular, compound 10y exhibited excellent antibacterial activity in comparison to others.