We tested methyl tertiary butyl ether both in vitro and in vivo to evaluate its efficacy as a potential cholesterol gallstone solvent for direct instillation into the human gallbladder or bile duct. Like diethyl ether, methyl tertiary butyl ether is an aliphatic ether with an excellent cholesterol-solubilizing capacity. However, unlike diethyl ether which vaporizes at body temperature, methyl tertiary butyl ether remains a liquid having a boiling point of 55.2 degrees C. In vitro, methyl tertiary butyl ether dissolved human gallstones (40%-94% cholesterol) within 60-100 min. In contrast, monooctanoin, an established gallstone solvent, required greater than 50 h to dissolve similar stones. By direct catheter instillation in 6 dogs, methyl tertiary butyl ether required only 4-16 h to dissolve gallstones surgically implanted in the gallbladder. The dogs tolerated methyl tertiary butyl ether with only minor clinical, biochemical, or histologic effects. We conclude that further evaluation of methyl tertiary butyl ether for dissolution of human gallbladder and biliary duct cholesterol stones is warranted.