Focal crypt injury by neutrophils (cryptitis/crypt abscesses), or focal active colitis (FAC), is a common isolated finding in endoscopic colorectal biopsies. Focal active colitis is often thought of as a feature of Crohn's disease, but may also be seen in ischemia, infections, partially treated ulcerative colitis, and as an isolated finding in patients undergoing endoscopy to exclude neoplasia. Clinical, endoscopic, and pathological data were retrospectively reviewed from 49 patients with focal active colitis, who had no other diagnostic findings on colorectal biopsy and no history of chronic inflammatory bowel disease. The histological findings were correlated with clinical diagnoses. Follow-up information was available for 42 of 49 focal active colitis patients. None developed inflammatory bowel disease; however, 19 patients had an acute self-limited colitis-like diarrheal illness, 11 had incidental focal active colitis (patients without diarrhea that were endoscoped to exclude colonic neoplasia and found to have asymptomatic FAC), 6 had irritable bowel syndrome, 4 had antibiotic-associated colitis, and 2 had ischemic colitis. Twenty patients were immunosuppressed, and 19 were taking nonsteroidal anti-inflammatory drugs. No histological features predicted final diagnoses. FAC did not predict the development of chronic colitis, even when mild crypt distortion or slight basal plasmacytosis was present. The preponderance of acute self-limited colitis and antibiotic-associated colitis among the FAC patients, along with the high number of immunosuppressed patients, support the conclusion that most FAC cases are infectious. The incidental detection of FAC in patients undergoing endoscopy to exclude colonic neoplasia was not clinically significant. The role of nonsteroidal anti-inflammatory drugs in FAC deserves further study.