The clinical behavior of central giant cell granuloma (CGCG) of the jaws is variable and difficult to predict. Clinical data and follow-up information of 26 patients with CGCG were analyzed. Histologic features were correlated with the clinical course of the disease. In 16 patients the CGCGs were asymptomatic; 10 lesions presented with aggressive growth, pain, massive swelling, root resorption, cortical perforation, and/or recurrence. These patients were younger and the lesions were larger than in the nonaggressive group. The histomorphometric analysis proved a significant increase in large giant cells, fractional surface area, and mitotic activity in aggressive CGCG lesions. Immunohistologic investigation (Ki-67 and p53 stain) revealed no significant differences. After surgical treatment, 3 patients with aggressive lesions developed a recurrence. The data show that clinical and histomorphometric features may be reliable indicators for the differentiation between aggressive and nonaggressive CGCG. This should be accounted for to improve the individual planning of the treatment and follow-up.