Recent studies have suggested that one possible cause of keratoconus involves increased degradation of the corneal extracellular matrix. Most studies have examined corneas from patients with bilateral, sporadic keratoconus. In this report, both corneas from a 70-year-old man with a history of familial keratoconus and clinical signs of unilateral keratoconus were examined for gelatinase activity. Our results demonstrated a qualitative (three additional activity bands of 88, 92, and 100 kDa molecular weights) and quantitative differences (an apparent increase in overall amounts) in the gelatinolytic enzyme profiles of the affected keratoconus cornea as compared with his unaffected (nonkeratoconus) cornea, normal corneas, bilateral sporadic keratoconus corneas, and cultured keratocytes. In addition, gelatinolytic enzymes were more readily extracted from the affected cornea compared with controls. These data lend support to the hypothesis of a heterogeneous etiology for keratoconus and to previous suggestions that this disorder may be related to an alteration in extracellular matrix degradation.