Two cases of left lower quadrant appendicitis associated with situs inversus totalis are presented. Historic, genetic, and embryologic aspects of situs inversus, as well as recent theories regarding etiology are discussed. The clinical recognition of appendicitis in situs inversus is often difficult because of the unusual location of the appendix and abnormal pain localization. The differentiation of situs inversus totalis and abnormal rotation of the abdominal viscera (situs indeterminus) is important surgically because fixation of the midgut loop may be indicated in patients with situs indeterminus.