Malarone(™), a combination of atovaquone (AT) and proguanil (PR), is indicated for the prophylaxis and treatment of uncomplicated Plasmodium falciparum malaria. This study aimed to determine in vitro the feasibility of delivering the combination of AT and PR as a spray formulation via the sublingual route, using Franz diffusion cells incorporating porcine sublingual mucosa. Firstly, 1 mg mL(-1) of each drug in 20% 1,8-Cineole in ethanol was used; and secondly, 5 mg mL(-1) AT and 1 mg mL(-1) PR in 20% 1-methyl-2-pyrrolidone in ethanol was examined, dosed every 2 h over a 12-h period and receptor phase samples were analyzed by HPLC. From the first study, mean fluxes for AT and PR were 12.89 ± 1.2 and 5.88 ± 0.9 µg cm(-2) h(-1) respectively; pharmacokinetic calculations indicated that these fluxes were insufficient to achieve the target plasma concentrations for AT and PR of 1.4 µg mL(-1) and 200 ng mL(-1) respectively, in the treatment of falciparum malaria. However, in the second study, the fluxes of AT and PR increased to 50.92 ± 20.8 and 12.01 ± 1.5 µg cm(-2) h(-1) respectively, and pharmacokinetic calculations indicated that therapeutic plasma concentrations are attainable for pediatric application.