Dilution enthalpies of two penicillamine enantiomers, namely, D-penicillamine, L-penicillamine, and their racemate D,L-penicillamine, in N,N-dimethylformamide (DMF) + water mixtures of various compositions have been determined at 298.15 K respectively, using an isothermal titration calorimeter (MicroCal ITC200). According to the McMillan-Mayer theory, homochiral enthalpic pairwise interaction coefficients (h(XX)) of the three penicillamines in DMF + water mixtures of different mass fractions (w(DMF) = 0 to 0.3) have been calculated regressively. It is found that h(XX) coefficients of each enantiomer and their racemate change increasingly with h(DMF) to the maxima at w(DMF) = 0.20 and then decrease relatively rapidly, which follows the order h(LL) > h(DD) approximate to h(RR) > 0 (R represents the racemate mixture of penicillamine). The results are discussed from the point of view of competitive equilibrium between hydrophobic and hydrophilic interactions in solutions.