Microorganisms producing squalene synthase inhibitors were screened from soils. A high producer was selected and identified as a Streptomyces species. Two active inhibitors were obtained from culture broths via a series of purification processes involving solvent extraction, WK-10 cation-exchange column chromatography, HP-20 adsorption column chromatography, silica-gel column chromatography, preparative HPLC, and crystallization. The inhibitors were confirmed as macrolactins A and F with molecular weights of 402 by UV-absorption spectrometry, fast atom bombardment mass spectometry, and 13C- and 1H-NMR analyses. Kinetic results for macrolactins A and F showed that they appear to be noncompetitive inhibitors of rat liver squalene synthase with IC50 values of 1.66 and 1.53 micromol/L, respectively. Since mammalian squalene synthase was used, these inhibitors have significant potential as therapeutic agents for hyperlipemia and suppression of cholesterol biosynthesis.