To determine the role of SPARC (secreted protein, acidic, and rich in cysteine) in cataractogenesis by examining mice deficient in a matricellular protein SPARC. Mice were rendered SPARC-deficient by a targeted disruption of the gene. Slit-lamp microscopy and histology were used to examine the eyes of SPARC-null and wild-type mice from birth to 14 months of age. SPARC-null mice developed opacities in the posterior cortex of the eye as early as 1.5 months after birth. The diffuse cataracts appeared to progress toward the anterior cortex and reached maturity in many animals by 3.5 months of age. Early stages of cataractogenesis in SPARC-null mice included inhibition of normal lens fiber cell differentiation, degeneration of fiber cells, vacuole formation at the equator, and liquefaction of the cortex. No cataracts were detected in wild-type mice up to the age of 8 months. The early onset of cataracts in SPARC-null mice establishes that the gene is essential to the maintenance of lens transparency.