To evaluate the histologic manifestations of collagenous colitis and correlate histologic changes with disease behavior, 14 patients who had undergone sequential evaluations during 33 +/- 6 months of follow-up were studied. Two hundred twelve tissue specimens from all anatomic regions of the colon (mean, 15 +/- 3 samples per patient) were interpretated independently under code by two pathologists. Eight patients (57%) had histologic resolution after 14 +/- 4 months of empiric therapy and in only one of these (12%) did symptoms persist. Four patients (29%) had sequential histologic examinations from the same anatomic region that varied from classical collagenous colitis to inflamed mucosa without a thickened collagen band to normal mucosa. Eight patients (57%) had varying histologic findings from different anatomic regions during the same examination that ranged from classical collagenous colitis to increased inflammation with resolution of the collagen band to normal mucosa. Normal mucosa was found mainly in specimens from the rectosigmoid, and proctosigmoidoscopic examinations alone would have missed the diagnosis of collagenous colitis in 40% of cases. Pathologic interpretations were concordant in 171 of 212 instances (81%). We conclude that histologic resolution of collagenous colitis can occur and it is associated with loss of symptoms. The histologic features of collagenous colitis are distinctive, but they may be patchy and inconsistently sampled. Rectosigmoid biopsies underestimate the diagnosis.