COCALD, an X-linked disorder with mean onset of 7 yrs, results in adrenal insufficiency and neurological deterioration. Without HSCT, death occurs within months to several years after clinical onset. In young men with adrenomyeloneuropathy who experience progressive paraparesis and sphincter disturbance due to spinal cord involvement over a period of decades, HSCT is not beneficial. Ninety-four boys have received HSCT from 07/81 to 08/97 to treat COCALD. Eighty-five patients engrafted after the first HSCT. The 5-year actuarial probability of survival is 55% (95% CI, 42% to 68%). A multivariate model confirmed that boys greater than 12 yrs of age were at the highest risk for death (RR=7) as compared to patients less than 7 yrs of age (P=0.004). Boys between 7 and 11 yrs of age were also at increased risk of death as compared to those less than 7 yrs (RR=3.4, P=0.05). Thirty-four of 46 evaluable, engrafted survivors are stable or improved with respect to neurological/neuropsychological status, of whom 15 have been followed more than 4.5 yrs. Boys with impaired neuropsychological function (performance IQ below 80) prior to HSCT have become vegetative or died shortly after transplant using historical HSCT methods. In contrast, successful HSCT in boys with PIQ above 80 has lead to favorable outcomes. We recommend that HSCT be performed when neuropsychological deterioration has been documented. MRI abnormality alone is an insufficient criterion for HSCT. We also recommend: selecting an appropriate HLA-genotypically identical sibling or matched unrelated donor of hematopoietic stem cells, improving membrane abnormalities by using GTO:GTE (Lorenzo's oil) for 2 months prior to HSCT and avoiding intralipid during HSCT, minimizing or preventing GVHD by T-lymphocyte depletion of donor marrow and short term methylprednisolone and continuous infusion CSA for prophylaxis, a preparative regimen of cyclophosphamide 60 mg/kg × 2 days, TBI 1400 cGy (7 fractions) sparing the brain while treating the skull (accomplished with tangential skull photons and temporal skull electron beam boosts). This new regimen was used in 6 boys with compromised PIQs before HSCT who have been studied at 6 to 17 months following HSCT. These 6 boys demonstrate stability in clinical status in contrast to many boys with moderate to advanced disease whose immediate post-HSCT clinical course has been marked by severe, rapid deterioration. To determine conditions for optimal HSCT, an international clinical trial with uniform data collection is needed.