To refine the pathologic diagnosis of collagenous colitis and to determine whether increased subepithelial collagen deposition (SCD) is specific for collagenous colitis (CC), we reviewed histologic sections of 1549 colonic mucosal biopsy procedures obtained from 1332 patients and 157 consecutive colonic resections. Quantitative evaluation of SCD was performed for those patients who showed thickness of SCD that was 5 microns or greater in either biopsies or resections, and the overall histologic and clinical features were correlated. A focal or diffuse increase of SCD greater than or equal to 5 microns was noted in 22 (1.7%) of the patients with biopsies and in 11 (7%) of the cases with resections. An otherwise unexplained, prolonged watery diarrhea was present in 6 (27%) of the 22 biopsy patients but in none of the patients with resections. These 6 patients with unexplained watery diarrhea had significantly greater amounts of SCD than those without this clinical feature both in terms of average thickness (21 microns versus 11 microns; P less than 0.02) and of the percentage of surface epithelium involved (47% versus 15%; P less than 0.02). Also, biopsies and resections with increased SCD from patients without watery diarrhea were all from the rectum and rectosigmoid region. These results lend further support to the nonspecificity of increased SCD and to the importance of the quantity of SCD, rather than its mere presence. In summary, increased SCD is not specific for CC; however, a greater amount of SCD is associated with a greater probability of associated watery diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)