Systematic inaccuracy is inherent in any computational estimate of a non-linear average, due to the availability of only a finite number of data values, N . Free energy differences ∆F between two states or systems are critically important examples of such averages in physical, chemical and biological settings. Previous work has demonstrated, empirically, that the "finite-sampling error" can be very large -many times kBT -in ∆F estimates for simple molecular systems. Here, we present a theoretical description of the inaccuracy, including the exact solution of a sample problem, the precise asymptotic behavior in terms of 1/N for large N , the identification of universal law, and numerical illustrations. The theory relies on corrections to the central and other limit theorems, and thus a role is played by stable (Lévy) probability distributions.Introduction. Free energy difference calculations have a tremendous range of applications in physical, chemical, and biological systems; examples include computations relating magnetic phases, estimates of chemical potentials, and of binding affinities of ligands to proteins (e.g., [1][2][3][4][5][6]). Since the work of Kirkwood [7], it has been appreciated that the free energy difference, ∆F ≡ ∆F 0→1 , of switching from a Hamiltonian H 0 to H 1 is given by a non-linear average,