While systemic autoimmune diseases are the main possibilities in the differential diagnosis of scleritis, other less common etiologies such as infections must also be considered. The authors report four cases of infectious scleritis to review predisposing factors, clinical characteristics, methods of diagnostic approach, and response to therapy. Two patients had primary scleritis and two patients had secondary scleritis following extension of primary corneal infection (corneoscleritis). Diagnoses included three local infections (one each with Staphylococcus. Acanthamoeba, and herpes simplex) and one systemic infection (Lyme disease). Stains, cultures, or immunologic studies from scleral, conjunctival, and/or corneal tissues, and serologic tests were used to make the diagnosis. Medical therapy, including antimicrobial agents, was instituted in all patients, and surgical procedures were additionally required in two patients (scleral grafting in one and two penetrating keratoplasties in another); the patient who required two penetrating keratoplasties had corneoscleritis and underwent eventual enucleation. Infectious agents should be considered in the differential diagnosis of scleritis.