Protein concentration influences nucleation and crystal growth rates, therefore an appropriate degree of supersaturation is essential for the preparation of large and good quality crystals. Knowledge of a protein's solubility dependence on solution variables such as temperature, pH, or ionic strength can be very useful for defining optimum conditions for protein crystal growth work. We have refined a Michaelson interferometry technique reported by Sazaki et al. (J. Crystal Growth 169 (1996) 355.) for determination of protein solubility using the proteins lysozyme and equine serum albumin by examining the behavior of both surface and concentration gradient fringes. This has provided a sensitive and accurate estimate of protein solubility using small crystals (0.2 mm x 0.1 mm).