Acanthamoeba infection of the cornea is an entity now recognized with increasing frequency. We saw two cases of Acanthamoeba sclerokeratitis in contact lens wearers in whom scleritis (anterior and posterior) played a central role in the clinical course of the disease. Scleritis is probably a more common component of Acanthamoeba infection than has generally been acknowledged. Posterior scleritis has not, to our knowledge, been reported previously in this disorder. The clinical diagnosis of Acanthamoeba infection has often been missed due to lack of a definition of the historical and clinical criteria by which this disease is characterized. We reviewed the 26 previously reported cases and suggest a set of criteria that can be used to establish an early diagnosis. Historical criteria include minor corneal trauma, exposure to soil or standing water, or contact lens wear. Clinical characteristics include severe pain, infiltrative (often ring-shaped) stromal keratitis, variable anterior uveitis, epithelial erosion, scleritis, standard bacterial culture negativity, chronicity, and lack of response to antimicrobial agents.