Myxoid mesenchymal lesions of the uterus are generally restricted to tumors, but non-neoplastic myxoid mesenchymal lesions of the uterus have not received much attention in the literature. We analyzed the clinicopathologic features of 2 patients with lupus erythematosus (ages 43 and 52 yr, respectively) in whom myometrial myxoidosis produced a markedly enlarged uterus with myometrial thickening ("secondary myometrial hypertrophy"). Both patients underwent a hysterectomy for presumed leiomyomas, and intraoperatively an enlarged uterus was noted. On gross examination, the uteri measured 13.5 x 13.5 x 11.5 cm and 14.5 x 11.5 x 9.5 cm, respectively. The significantly thickened myometrium was due to marked expansion of the interstitial compartment of the myometrium, in which non-neoplastic smooth muscle fascicles were widely separated by abundant extracellular mucin producing a striking myxoid appearance ("myxoidosis"). These histologic findings are akin to the pattern of dermal mucin deposition seen in lupus erythematosus. The lesion in each case diffusely involved the entire myometrium. Histochemical stains were performed and showed the following results: mucicarmine-diffusely but weakly positive; periodic acid-schiff (PAS)-negative; colloidal iron-diffuse positive; alcian blue, pH 2.5 (without hyaluronidase digestion)-diffuse positive, and alcian blue, pH 2.5 (with hyaluronidase digestion)-negative. These histochemical findings are consistent with hyaluronic acid. Follow-up in 1 case was not available. In the other case, the patient presented to clinical attention 5 weeks after surgery because of ascites, which after an extensive clinical evaluation was interpreted as being of unknown etiology. To the best of our knowledge, this rare and unusual non-neoplastic myometrial lesion has not been previously described. Pathologists should be aware of its existence because of the distinctive appearance and as it may prompt consideration of various myxoid neoplasms of the uterus in the differential diagnosis. Patients with myometrial myxoidosis should be evaluated for lupus erythematosus.