Multinucleate cell angiohistiocytoma (MCAH) is a vascular and fibrohistiocytic proliferation with unknown pathogenesis. Clinical lesions tend to be localized to an anatomical area. Exceptionally, the generalized variant is rare. This study reports three cases of generalized MCAH, and analyzes the clinicopathological features of 15 cases reviewed in the published work. Compared with the localized variant, generalized MCAH affected both sexes equally, had an earlier age of onset and a predilection for the trunk and extremities. Histopathologically, the most characteristic feature is the giant, bizarre multinucleate cells with angulated cytoplasm. Systemic diseases or abnormal immune conditions were revealed in six patients with generalized MCAH. For the first time, we found that the present cases showed increased elastic fibers in the affected areas, suggesting that the synthetic function of fibroblasts was active. This study suggested that MCAH originates from fibroblasts and is a distinct entity with potential correlation with abnormal immune states.