Despite improvements in medical therapy and availabilty of cardiac transplants, primary cardiomyopathy[CMP] continues as a leading cardiac cause of death in children. Recent studies indicate a familial etiology in 20-30%. Mitochondrial long chain fatty acid oxidation is crucial to cardiac energy production in extrauterine life, and defects in this pathway have been associated with cardiomyopathy, skeletal myopathy, Reye-like syndrome of hepatic encephalopathy and sudden death. Very long chain acyl-CoA dehydrogenase [VLCAD] catalyses the first step in the β-oxidation spiral of fatty acid oxidation. We studied thirty seven families with patients who had clinical and biochemical features suggestive of a long chain fatty acid oxidation defect. Mutations on the VLCAD gene were identified in eighteen patients. Sixty six percent[12/18] of patients had CMP. Ten patients presented with dilated CMP and 2 had hypertrophic CMP. Eight[66%] of these patients survived the acute episode and on followup six[50%] have normal cardiac function. Thirty three percent of patients[6/18] had hepatic abnormalities and 16% skeletal myopathy. Three patients were diagnosed following sudden death. The overall mortality in VLCAD deficiency was 7/18[36%]. To define VLCAD mutations, initial screening of genomic DNA was performed using single stranded conformational variance[SSCV] on all 20 exons of the VLCAD gene. Two patients were homozygous. Using direct sequencing and subcloning, we have defined both allelic mutations in nine and single allele mutations in seven of the compound heterozygote patients. We have identified 21 different mutations on the VLCAD gene, most[85%] of which result in a severe CMP phenotye which presents early in infancy. Early recognition and aggressive medical support, in the acute phase of illness, is essential for patient survival.