The macrolide antibiotics, erythromycin and azithromycin, have been studied for their potential antimalarial activity, but only modest activity has been demonstrated. In this study, we investigated the enhancement of the efficacy of these antibiotics in combination with a patented lipid-based drug delivery system, Pheroid technology. A chloroquine resistant strain of Plasmodium falciparum (RSA11) was incubated with the formulations for a prolonged incubation time (144 h). Drug efficacy assays were conducted by analyzing the histidine-rich protein II levels of the parasites. The effects of azithromycin and erythromycin were compared with other antibiotics and standard antimalarial drugs. The poor water soluble nature of the drugs led to the formation of micro scale Pheroid vesicles with average particle sizes of 72.76±10.73 lm for azithromycin and 100.62±29.27 lm for erythromycin. The IC 50 values of erythromycin and azithromycin alone and entrapped in Pheroid vesicles decreased statistically significant (Pp0.05). Prolonged exposure was also statistically meaningful (Pp0.05), although it seems that exposure need not exceed 96 h. Pheroid vesicles also proved successful in decreasing the IC 50 values of doxycycline, tetracycline and triclosan. Pheroid vesicles containing antibiotics could prove successful as a malaria treatment option.