The distribution of lipid in the fetal adrenal cortex is reported to correlate with the duration of hypoxia and degree of fetal stress. The original studies were based on Oil Red O staining, requiring frozen tissue that is often not available. To investigate the reliability of these observations, the distribution of lipid in the fetal adrenal cortex was studied in hydrops fetalis (HF) of different etiologies, using immunostaining for adipophilin on formalin-fixed material. Twenty cases of HF due to hemoglobin (Hb) Bart were compared to 34 cases of HF due to other causes. In the fetal zone, lipid distribution was more diffuse in Hb Bart HF compared to other causes of HF, including those due to anemia, supporting the concept that increased lipid in the fetal zone is associated with severity of hypoxia. A more diffuse distribution of lipid correlated with adrenal cytomegaly (P < 0.01) and extramedullary hematopoiesis (P < 0.01) but not Hb level (P = 0.68) nor compact cell change (P = 0.7) or cystic degeneration (P = 0.07) in the definitive zone. A greater degree of cystic degeneration correlated with lower gestational age, rather than the specific etiology of HF. Thus, cystic degeneration is more a reflection of the onset of fetal stress than severity. The combined histologic changes in the fetal and definitive zones of the adrenal gland provide complementary information about fetal status in HF. Immnunostaining for adipophilin circumvents the need for frozen tissue for assessing lipid content by Oil Red O staining, facilitating studies based on archival material.