Lipoblastoma (LPB) is a benign neoplasm that occurs predominantly in early childhood. We investigated clinicopathologic features, associated conditions, immunohistochemistry, and outcome in 59 LPB identified from surgical pathology and consultation files. Pathology materials, cytogenetics reports, and medical records were reviewed. Immunohistochemistry for S100 protein, CD34, and Mib-1 was performed on formalin-fixed, paraffin-embedded tissue using standard techniques. Fifty-nine patients had 74 samples, including 14 patients with one or more with local recurrences among the 30 patients who had available follow-up information. There were 37 males and 22 females (ratio 1.7). Age at diagnosis ranged from 3 months to 16 years with 22% in the first year, 68% at 1 to 9 years, and 10% at 10 to 16 years. Sixty-four percent arose on the trunk, 27% on the extremities, and 8% in the head/neck. Forty-six percent had one or more recurrences. Tumor diameter ranged from 1.2 to 15.5 cm. The white to yellow cut surface showed variable lobulation and myxoid change. Histologically, nodules of adipose and myxoid tissue were demarcated by bands of fibrous tissue. The cells displayed a range of differentiation from multivacuolated lipoblasts to mature adipocytes. Mitoses were nonexistent to rare. Histologic variations included a subtle zonal architecture of fat maturation, abundant myxoid material, primitive mesenchymal cells, a focal plexiform vascular pattern, and multinucleated cells. All cases tested were immunoreactive for S100 and CD34; Mib-1 reactivity was absent to low. Cytogenetic aberrations included chromosome 8 abnormalities in 8 cases, nonspecific numerical abnormalities in 1 case, and a normal karyotype in 1 case. Ten patients had other medical conditions including macrocephaly, seizures, developmental delay, autism, congenital anomalies, Sturge-Weber syndrome, or a family history of multiple lipomas. In summary, this large series of LPB demonstrates its occurrence in older children and adolescents, documents a recurrence rate of 46% and confirms that the degree of adipocytic differentiation does not predict biologic behavior. An unexpected finding was the presence in 17% of patients of central nervous system disorders such as seizures, autism, and developmental delay, congenital anomalies, Sturge-Weber syndrome, or a family history of lipomas. These observations raise the question of whether predisposing genetic or other constitutional factors contribute to the development of LPB or whether LPB is indicative of a syndrome.