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Very long chain acyl-CoA dehydrogenase (VLCAD) catalyses the first step of the betaoxidation spiral of fatty acid metabolism. Its deficiency is associated with sudden infant death syndrome, cardiomyopathy, Reye Syndrome-like hepatic encephalopathy, and skeletal myopathy. To investigate the molecular basis of VLCAD deficiency, we isolated and completely sequenced the human VLCAD cDNA and gene. With these data, we screened fifteen patients with clinical and biochemical evidence suggestive of VLCAD deficiency using single stranded conformational variance (SSCV) for all 20 exons and identified abnormalities in fourteen patients. We also screened parents of two infants who died with clinical features consistent with VLCAD deficiency. Amplified PCR products were subcloned and sequenced by the dideoxy method for mutational analysis. Ten different mutations were found in nine patients. A C1837T,(R613W) mutation was present in three patients, and a 3-base pair deletion(delta 891-893) was found in two. One patient was homozygous for a mutation in the consensus dinucleotide of the donor splice site [g+1a] resulting in skipping of the prior exon [exon 11]. Four patients were compound heterozygotes and so far, single allele abnormalities have been found in four patients. Six patients have, as yet, unknown mutations. In all, nine patients presented with cardiomyopathy, six with skeletal myopathy, and four with a metabolic crisis. Four patients (22%) died. This study proves the heterogenous nature of the clinical features and the molecular defects in VLCAD deficiency.