Methyl tert-butyl ether (MTBE) is the solvent most commonly used for in vivo dissolution of cholesterol gallstones. Its limitations, however, include high volatility and flammability along with potential toxicologic concerns. Therapy may take several hours. This study was initiated to identify alternate solvents which may be superior to MTBE in one or more of these areas. MTBE was compared with several other solvents for cholesterol-dissolving capacity. Groups of human cholesterol gallstones were placed in test tubes, and, without agitation, subjected to mixtures of MTBE:ethanol or another solvent:ethanol. Six other solvents were found to have higher capacities. In several cases, other solvent mixtures dissolved gallstones up to twice as fast as the MTBE:ethanol mixture. These faster solvents were cyclic ethers (tetrahydrofuran [THF], methyl tetrahydrofuran [MTHF], tetrahydropyran [THP], methyl tetrahydropyran [MTHP], and possibly dimethyl tetrahydrofuran [DMTHF]) and limonene. Some of these solvents also have lower volatility and higher flash points than MTBE, resulting in safer storage and handling. THF and pyridine, however, were found to precipitate bile components when mixed with bile. The authors describe solvents that may be superior to MTBE for rapid dissolution of gallstones in vivo.