The compound naphthoquine phosphate is a novel antimalaria drug tablet containing a fixed-dose combination of naphthoquine phosphate and artemisinin in a 1:2.5 ratio. A randomized, open study on the safety and tolerability was conducted in 28 healthy male volunteers using a single oral dose of 350 mg, 700 mg, 1400 mg, or 2100 mg of artemisinin-naphthoquine phosphate. Pharmacokinetics at the last 3 doses were examined in 30 volunteers. Food effects were also determined. Serial blood samples up to 216 hours after single oral dose administration were analyzed for plasma concentrations using a validated high-performance liquid chromatography-tandem mass spectrometry assay. The compound was well tolerated at single doses up to 2100 mg. Increased exposure to naphthoquine phosphate and artemisinin was less than dose proportional and linear. The half-life of naphthoquine phosphate was approximately 255 hours. The combination increased the AUC(0-t) and C(max) of both artemisinin (by 71% and 49%) and naphthoquine phosphate (by 135% and 104%) compared with monotherapy. Food intake greatly increased the AUC(0-t) of artemisinin with a ratio of 77% and reduced that of naphthoquine phosphate from 955 ± 352 µg·h/L under the fasted state to 446 ± 231 µg·h/L in the fed condition. The pharmacokinetics and safety profile of the drug support its continued investigation in future clinical studies.