The purpose of this study was to compare the in vitro activity of a new ketolide, HMR 3004 (RU64004), to that of three macrolides and one azalide against 608 Streptococcus pneumoniae and 202 Haemophilus influenzae. Macrolide-resistant pneumococci were susceptible to HMR 3004, even if they were resistant to clindamycin, Against Haemophilus influenzae, HMR 3004 and azithromycin were nearly identical in potency; the macrolides were 8- to 16-fold less active, HMR 3004 may be useful for treating respiratory tract infections if sufficient concentrations can be achieved at the local sites of infection.