To establish a framework for extrapolating the helix-forming properties of peptides from TFE/H2O mixtures (TFE = 2,2, 2-trifluoroethanol) back to water, the thermal unfolding curves have been measured by circular dichroism for four repeating-sequence peptides, with chain lengths from 7 to 22 residues. The unfolding curves were measured between 0 and 50 volume percent TFE and were fitted to the modified Lifson-Roig theory. A single set of helix-coil parameters fits the results for the four peptides at each TFE concentration; only two of the basic helix-coil parameters, <w>, the mean helix propagation parameter of residues in the sequence repeat, and DeltaH, the enthalpy change per residue on unfolding the helix, are allowed to vary with TFE molarity. The success in fitting these curves over a wide range of experimental variables shows that helix formation is basically the same in TFE/H2O mixtures as in water. Moreover, a simple model based on a linear dependence of ln <w> and DeltaH on TFE molarity can be used to extrapolate the results from 25% TFE (approximately 4 M) back to water. The results also give curves of helix formation induced by TFE at constant temperature, and the properties of these helix induction curves explain some of the puzzling results shown by other peptides in the literature. The average helix propensity increases regularly from 0 to 25% TFE but levels off at higher TFE concentrations, which explains why the extent of helix formation levels off in this range. The change in the apparent cooperativity of thermal unfolding curves in concentrated TFE solutions results from the decrease of the enthalpy change for helix unfolding at higher TFE concentrations. The rapid decrease in the plateau values of apparent helix content with increasing temperature results mainly from the strong temperature dependence of the ellipticity of the complete helix. To determine whether the helix-stabilizing effect of TFE arises from strengthening the hydrogen bonds in the helix backbone, the strength of the hydrogen bond in a model compound, salicylic acid, has been measured in TFE/H2O mixtures from the pKa difference between salicylic acid and a similar compound which cannot form the hydrogen bond. The curve of hydrogen bond strength versus increasing TFE concentration matches both in shape and magnitude the increase in average helix propensity in TFE/H2O mixtures.