Supercritical fluid chromatography (SFC) with electron-capture detection is described for the sensitive quantification of mefloquine in 0.1-ml blood samples. The method is internally standardized and incorporates partitioning into methyl tert.-butyl ether (MTBE) from aqueous base, back-extraction into dilute aqueous acid and final partitioning into MTBE from aqueous base. SFC conditions include a silica-gel-packed, glass-lined steel column and a mobile phase of 0.15% n-butylamine and 1% methanol in supercritical n-pentane. The method has a detection limit of 7.5 ng/ml in 0.1-ml blood samples and exhibits good linearity and precision. The method compares favorably with a published high-performance liquid chromatographic procedure in the analysis of blood from volunteers who received mefloquine hydrochloride (15 mg as base per kg body weight).