Genetic variants may underlie sporadic amyotrophic lateral sclerosis (SALS), but in only a few percent of patients have causative mutations been found. This is possibly because SALS is more often due to a variation in DNA methylation, an epigenetic phenomenon involved in gene silencing. Methylation across the whole genome was examined in brain DNA of 10 SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated by Affymetrix GeneChip Human Tiling 2.0R Arrays. Methylation levels were compared between SALS patients and controls at each region of methylation across the genome. SALS patients had either hypo- or hyper-methylation at 38 methylation sites (p </= 0.01). Of these, 23 were associated with genes and three with CpG islands. Pathway analysis showed that genes with different methylation in SALS were particularly involved in calcium homeostasis, neurotransmission and oxidative stress. In conclusion, a number of genes, either unsuspected in SALS or in potential cell death pathways, showed altered methylation in SALS brains. The possibility of epigenetic therapy for SALS should encourage confirmation of these initial results in a future larger whole-genome DNA methylation study.