Artemisinin (Qinghaosu, 1) is a sesquiterpene lactone endoperoxide isolated from Artemisia annua L. that Chinese herbalists have traditionally used to treat malaria. Reduction of artemisinin by NaBH(4) produced dihydroartemisinin (DHA, 2) and yielded a new stereochemically labile center at C-10, which in turn provided two lactol hemiacetal interconverting epimers, namely, 2α and 2β. With the aim of fully investigating the thermodynamics of interconversion, we gathered the relative abundance of the two epimers within a wide variety of solvents and rationalized the results by linear solvation energy relationships (LSER) analysis. Beside the difference in polarity, the better stabilization of 2α in polar solvents was found to be significantly related to its greater acidity with respect to 2β, which was estimated by two independent theoretical approaches based on molecular modeling calculations and empirical data, and supported by (1)H NMR measurements. On the contrary, differential effects of cavitational energy have been highlighted as interactions strongly responsible for the small values of equilibrium constant measured for the β ⇆ α process in the less polar media. Determination of forward and backward epimerization rate constants in seven media, clearly differing in both permittivity and capacity to be H-bond donors, indicated that, in the spontaneous process, the transition state of the rate-limiting step develops a significant degree of anionic character, as typically happens in the base-catalyzed breakdown of hemiacetals.