A general concern in the lyophilization of protein pharmaceuticals is how dry a product should be in order to maintain its stability during storage. This paper presents our exploratory studies on determining if there is an optimal residual moisture content for lyophilized recombinant protein products. The proteins used in this study were methionyl human growth hormone (met-hGH) and tissue type plasminogen activator (tPA). The amount of water adsorbed on each protein can be determined and approximated as a monolayer by the Brunauer-Emmett-Teller method. The result was in good agreement with the theoretical value calculated from the total number of strong polar groups in the molecule without regard to the conformation of the protein. This approach suggests that each protein may have a minimum moisture content that is necessary to shield the polar groups, and that over-drying will lead to exposure of these groups. The effect of residual moisture content on the stability of tPA in lyophilized excipient-free powder was studied. Samples that were dried to a water content below the calculated monolayer exhibited opalescence upon reconstitution, while those that were dried to either monolayer or multilayer water content tended to show a greater loss in biological stability upon storage under temperature stress conditions. The results of our studies reveal that the generally accepted concept "the drier the better" may not be appropriate for tPA. An optimum residual moisture content is required to balance the physical stability and the biological stability. These observations may apply to other protein products as well.