We investigate enthalpy-entropy compensation for melting of nearest-neighbor doublets in DNA. Based on data for 10 normal doublets and for doublets containing a mispaired or analog base, the correlation of delta Szero with delta Hzero follows a rectangular hyperbola. Doublet melting temperature relates linearly to delta Hzero by Tm = T(o) + delta Hzero/a, where T(o) = 273 K and a = 80 cal/mol-K. Thus Tm is proportional to delta Hzero + aTo rather than to delta Hzero alone as previously thought by assuming delta Szero to be constant. The term aTo = 21.8 kcal/mol may reflect a constant enthalpy change in solvent accompanying the DNA enthalpy change for doublet melting and is roughly equivalent to breaking four H-bonds between water molecules for each melted doublet. The solvent entropy change (aTo/Tm) declines with increasing Tm, while the DNA entropy change (delta Hzero/Tm) rises, so the combined DNA + solvent entropy change stays constant at 80 cal/K/mol of doublet. If such constancy in DNA + solvent entropy changes also holds for enzyme clefts as "solvent," then free energy differences for competing correct and incorrect base pairs in polymerase clefts may be as large as enthalpy differences and possibly sufficient to account for DNA polymerase accuracy. The hyperbolic relationship between delta Szero and delta Hzero observed in 1 M salt can be used to evaluate delta Hzero and delta Szero from Tm at lower, physiologically relevant, salt concentrations.