Keratoconjunctivitis sicca complicates both scleroderma and Sjögren's syndrome. Scleroderma of recent onset is difficult to diagnose, but is easily recognized late in its course. To assess the value of the conjunctival biopsy in the diagnosis of scleroderma, we used light, scanning, and transmission electron microscopy to compare in a masked fashion specimens from 21 patients with scleroderma and 14 patients with primary Sjögren's syndrome. Epithelial changes permitted diagnosis of early scleroderma in the two groups of patients. Lymphocytic infiltrate was always present in Sjögren's syndrome, but not in scleroderma. Fibrosis was always found in scleroderma, even in scleroderma of recent onset, but was absent in Sjögren's syndrome. The fibrosis was distributed around capillaries in a band-like pattern and was associated with degranulating mast cells. Conjunctival biopsy is valuable for the early diagnosis of scleroderma and for differentiating between scleroderma and primary Sjögren's syndrome.