Studies with laboratory animals have demonstrated fatal neurotoxicity that is associated with administration of artemether (AM) and arteether (AE) intramuscularly or artelinic acid (AL) orally. Toxicokinetic studies showed oil-soluble artemisinins form a depot at the intramuscular injection sites, which is associated with fascia inflammation in muscles. Oral administration of AL induces a gastrointestinal toxicity that is linked with delayed gastric emptying. These effects suggest that the exposure time of artemisinins was extended due to drug accumulation in blood, and this in turn resulted in neurotoxicity. In the present report, the drug exposure time with a neurotoxic outcome (neurotoxic exposure time) was evaluated as a predictor of neurotoxicity in vivo. The neurotoxic exposure time represents a total time spent above a lowest observed neurotoxic effect levels (LONEL) in plasma. The dose of AE required to induce minimal neurotoxicity requires a 2-3 fold longer exposure time in rhesus monkeys (179.5 h) than in rats (67.1 h) and dogs (103.7 h) by using a daily dose of 6-12.5 mg/kg for 7-28 days, indicating that the safe dosing duration in monkeys should be longer than 7 days under the exposure. The neurotoxic exposure time of artemisinins could be longer in humans as the comparison of monkeys to humans is likely more relevant than from rodents or dogs. Oral AL required much longer exposure times (8-fold) than intramuscular AE to induce neurotoxicity, suggesting that water-soluble artemisinins appear to be much safer than oil-soluble artemisinins. Due to lower doses (2-4 mg/kg) used with current artemisinins and the more rare use of AE in treating humans the exposure time is much shorter in humans. Therefore, the current regimen of 3-5 days dosing duration should be quite safe. These findings support a recently published WHO guide for malaria treatment with artemisinin regimens, such as artemisinin-based combination therapies and injectable artesunate, to avoid neurotoxicity.