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The gene SURF1encodes a factor involved in the biogenesis of cytochrome coxidase, the last complex in the respiratory chain. Mutations of theSURF1gene result in Leigh syndrome and severe cytochromecoxidase deficiency. Analysis of seven unrelated patients with cytochrome coxidase deficiency and typical Leigh syndrome revealed different SURF1mutations in four of them. Only these four cases had associated demyelinating neuropathy. Three mutations were novel splicing-site mutations that lead to the excision of exon 6. Two different novel heterozygous mutations were found at the same guanine residue at the donor splice site of intron 6; one was a deletion, whereas the other was a transition [588+1G>A]. The third novel splicing-site mutation was a homozygous [516–2_516–1delAG] in intron 5. One patient only had a homozygous polymorphism in the middle of the intron 8 [835+25C>T]. Western blot analysis showed that Surf1 protein was absent in all four patients harboring mutations. Our studies confirm that theSURF1gene is an important nuclear gene involved in the cytochrome coxidase deficiency. We also show that Surf1 protein is not implicated in the assembly of other respiratory chain complexes or the pyruvate dehydrogenase complex.