Focal active colitis (FAC) is a common pattern of injury in colorectal biopsy specimens. Recently, FAC was found to be a marker of an infectious colitis-like diarrheal illness and ischemic colitis but not of Crohn's disease. We evaluated 31 cases of FAC at the Cleveland Clinic Foundation, Cleveland. Ohio, between 1982 and 1992, to assess the clinical significance of this histologic finding. We evaluated the degree of neutrophil-mediated crypt epithelial injury, the degree of neutrophil-mediated surface epithelial injury, and the lamina propria cellularity and cell type. In each biopsy specimen, all of the above features were scored as 1+ (involving < 10%), 2+ (10-25%), or 3+ (26-50%) of the specimen. Clinical follow-up for the 31 patients ranged from 1 to 51 months (mean, 26 mo). Clinical diagnoses included infectious-type colitis (15 cases, 48%); incidental FAC (9 cases, 29%), occurring in asymptomatic patients undergoing screening for colonic neoplasia; ischemic colitis (3 cases, 10%); and Crohn's disease (4 cases, 13%). Histologically, all of the cases had some degree of cryptitis, and 24 (77%) of the 31 had neutrophil-mediated surface epithelial injury. In 13 (42%) of the 31, there was an expansion of the lamina propria by neutrophils, in 12 (39%) by eosinophils, and in 11 (35%) by plasma cells. None of the histologic features correlated with specific clinical diagnostic categories (Fisher's exact test). In conclusion, FAC most commonly correlates clinically with an infectious-type of colitis. On occasion, FAC might be a harbinger of Crohn's disease. Histologic features are not useful in predicting specific clinical diagnoses as a correlate to FAC.