A quadruple mutant of staphylococcal nuclease, nuclease (V66L/G79S/G88V/L108V), has been crystallized in a form well suited to moderate-to-high resolution x-ray diffraction analysis. This mutant is highly unstable; only about 20% of the protein in solution at room temperature is in its folded form. Under the crystallization conditions, the protein exhibits circular dichroism properties similar to, but not identical with, those of native wild type protein. The crystals belong to the space group P6(1)22 or P6(5)22 with unit cell dimensions of a = b = 61.1 A, c = 170.1 A and diffract to at least 2.5 A resolution. A data set complete to 3.7 A resolution has been collected and processed; attempts to determine the structure using molecular replacement techniques are under way.