The pharmacokinetics of sublingual artemether (ArTiMist™) were investigated in two open-label studies. In Study 1, 16 healthy males were randomized to each of four single-dose treatments administered in random order; i) 15.0 mg sublingual artemether (5 x 3.0 actuations), ii) 30.0 mg sublingual artemether (10 x 3.0 mg), iii) 30.0 mg sublingual artemether (5 x 6.0 mg), and iv) 30.0 mg artemether as tablets. In Study 2, 16 healthy males were randomized to eight 30.0 mg doses of sublingual artemether given over 5 days as either 10 x 3.0 mg or 5 x 6.0 mg actuations. Frequent blood samples were drawn post-dose. Plasma artemether and dihydroartemisinin were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In Study 1, sublingual artemether absorption was biphasic with both rate constants greater than that of artemether tablets (1.46 and 1.66 vs 0.43/h, respectively). Relative to tablets, sublingual artemether had greater bioavailability (≥1.24) with greatest relative bioavailability in the 30.0 mg dose groups (≥1.58). In Study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism in later vs earlier doses but no difference in bioavailability between dose actuations. Sublingual artemether is more rapidly and completely absorbed than equivalent doses of artemether tablets in healthy adults. Its disposition appears complex with two absorption phases, the first representing pre-gastrointestinal absorption, as well as dose-dependent bioavailability and auto-induction of metabolism with multiple dosing.