The influence of external cosolutes on the thermal stability of the B1 domain of protein L (ProtL) has been studied by circular dichroism, fluorescence spectroscopy, and differential scanning calorimetry. The thermal denaturation midpoint is effectively modulated by the addition of a suite of anions and follows the Hofmeister series. The maximum increase in thermostability (corresponding to 14 degrees C) was observed in the presence of 1 M sodium sulfate. After conversion of the experimental data into the change in the virial coefficient, a mechanistic model was used to estimate the relative contributions from excluded volume and preferential anion solvation for each anion. As expected, the excluded volume term stabilizes the native conformation of ProtL for all the cosolutes, but opposite effects on protein stability arise from the anion's solvation depending on their tendency to interact with or to become excluded from the protein surface. This behavior is in agreement with the results of independent NMR experiments: the anions that strongly interact with the protein surface produce significant perturbations in the amide protein chemical shift (delta d23(HN)). A correlation obtained between delta d23(HN) and the temperature coefficients for the different amide protons provides qualitative information about the structural determinants for the interaction between the protein surface and the cosolute.