Collagenous and lymphocytic colitis might be part of the same disease spectrum. In this report, we present a histopathologic subtype of microscopic colitis characterized by the presence of subepithelial multinucleated giant cells. This reaction is very unusual and not explicable by any underlying disease process or previous treatment. Among 490 cases of microscopic colitis (MC) diagnosed between 1992 and 2002, we found 2 cases with macrophages and giant cells (0.4%). One case of lymphocytic colitis (LC) and 1 case of collagenous colitis (CC) presented aggregates of macrophages and giant cells located in the superficial part of the lamina propria. Infectious or non-infectious colonic granulomatous diseases were excluded on histologic, clinical, and biological grounds. The recognition of this feature in an MC is important to avoid the diagnosis of granulomatous infectious or idiopathic colitis such as Crohn's disease. Even if very unusual, this subtype of MC evolves favorably since the 2 patients responded well to corticosteroid treatment