Calciphylaxis is characterized by ischemic necrosis, primarily of skin. The early phase of the ischemia has not been studied, and the pathogenesis is uncertain. In this study of early calciphylaxis, the vessels responsible for the ischemia seem to be within the material available for microscopic review, and the various stenosing vascular lesions are quantified. A distinctive and previously described small vessel calcification with superimposed endovascular fibrosis is most common, and is much more frequent than two other lesions proposed to cause the ischemia (thrombosis and global calcific obliteration). The calcified stenotic vessels average 100 microns in diameter. Calcification precedes the endovascular fibrosis. Vessels with early endovascular fibroblastic activation are found statistically to be strongly associated with the presence of a giant cell reaction. This endovascular giant cell reaction has not been previously described in calciphylaxis. Two additional cases show similar findings. The histology resembles the reaction to calcium in a variety of other extraosseous calcification syndromes, for example, pseudogout, as if calciphylaxis were an endovascular form of calcium crystal-induced inflammatory disease. The literature is reviewed, and the clinicopathologic, radiographic, and therapeutic implications are discussed.