Selection of biocompatible solvents is critical when designing bioprocessing applications for the in situ biphasic extraction of metabolic end-products. The prediction of the biocompatibility of supercritical and compressed solvents is more complicated than for liquid solvents, because their properties can change significantly with pressure and temperature. The activity of the anaerobic thermophilic bacterium, Clostridium thermocellum, was studied when the organism was incubated in the presence of compressed nitrogen, ethane, and propane at 333 K and multiple pressures. The metabolic activity of the organisms in contact with compressed solvents was analyzed using traditional indicators of solvent biocompatibility, such as log P, interfacial tension, and solvent density. The toxicity of the compressed solvents was compared with the phase and molecular toxicity effects measured in liquid alkanes at atmospheric pressure. Inactivation increased with time in the presence of the compressed solvents, but was constant in the presence of atmospheric liquid solvents. Knowledge of molecular and phase toxicity provides a framework for the interpretation of C. thermocellum metabolism in contact With atmospheric and compressed solvents.