The inflammatory myofibroblastic tumor (IMT) is a distinctive but controversial lesion, usually occurring during childhood, composed of fascicles of bland myofibroblastic cells admixed with a prominent inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils. Often affecting the lung and associated with constitutional symptoms, this lesion has been variously termed plasma cell granuloma, inflammatory pseudotumor, inflammatory myofibrohistiocytic proliferation, and inflammatory fibrosarcoma to reflect divergent views concerning its pathogenesis and level of malignancy. Cytogenetic analysis of an intra-abdominal myxoid hamartoma, a probable variant of this lesion, and a pulmonary IMT demonstrated clonal chromosomal abnormalities, lending support to the view that the IMT might be a neoplasm. There have been few cases studied to date, however, and the extent of cytogenetic anomalies in IMTs is not known. Karyotype analyses were performed on IMTs showing typical histologic features from three children. In addition, one case was studied by fluorescence in situ hybridization. Seventeen of 20 metaphase cells examined from a pulmonary IMT in a 5.5-year-old girl had an abnormal 47,XX+r(ring) karyotype. Fluorescence in situ hybridization studies demonstrated that the ring chromosome contained sequences of chromosome 8. Of 40 metaphase cells studied from a mesenteric IMT in an 8-month-old boy, 12 showed clonal aberrations, characterized as 43,XY,add(1)(p36),add(2)(p24),-6,der(14,22)(q10;q10),-19. Each of 20 metaphase cells examined from a retroperitoneal IMT in a 14-year-old girl contained complex clonal and nonclonal aberrations, characterized as 46-47,X,-X,add(2)(p22),add(2)(q13),+add(2)(q13),+5,-6,+i(7)(p10),add(8)( p11.2),+del(9)(p13),add(11)(p11.2)add(11)(q25),-13,-16,-18,add(19)(q13.1 ),add(19)(q13.1),+20,-21,-22,+mar1,+1-2mars. The presence of clonal chromosomal aberrations in all of the three tumors indicates that the IMT is a neoplastic proliferation.