Abstract Objective By a clinicopathologic study, to evaluate the histopathologic features associated with various causes of scleritis. Design Retrospective observational case series. Participants Enucleated globes or biopsy specimens obtained from 55 cases of clinically diagnosed necrotizing scleritis. Methods On the basis of their histologic appearance, these cases were divided into four morphologic groups: (1) zonal necrotizing granulomatous scleral inflammation; (2) nonzonal diffuse scleral inflammation, with or without granulomatous process; (3) necrotizing inflammation with microabscesses, with or without evidence of micro-organisms in the section studied; and (4) sarcoidal granulomatous inflammation. The clinical charts were reviewed for the presence of any associated disease. Results There were 14 (25.4%) cases in the first group; 12 had clinical evidence of systemic autoimmune diseases, including 8 cases of rheumatoid arthritis and 1 each of polychondritis, Goodpasture syndrome, Wegener granulomatosis, and collagen vascular disease; of the remaining 2 cases, 1 patient had a history of herpes zoster ophthalmicus, and the other had no history of any systemic autoimmune or infectious disease. None of the 19 (34.5%) patients characteristic of group 2 had any history of systemic autoimmune or infectious disease. Eleven of the 21 (38.2%) patients in group 3 had infections, including Pseudomonas spp., gram-positive cocci, Haemophilus spp., Actinomyces spp., and fungi; in the 10 remaining cases, no micro-organisms could be detected. The one case in group 4 was diagnosed as sarcoidosis. Conclusions On the basis of their histologic features, rheumatoid scleritis and related systemic autoimmune-mediated necrotizing scleral inflammations could be differentiated from either idiopathic or infectious scleritis; however, the histologic features of rheumatoid scleritis were similar to those of necrotizing scleritis associated with other systemic autoimmune diseases.