Retrotransposons (RTs) account for similar to 45% of the mammalian genome. They are capable of inserting into new genomic locations, which can result in deleterious outcomes. We examined the response of nine RTs to global cerebral ischemia (GCI) and explored the DNA methylation status of the two significantly altered RTs. Seven of the nine RTs were significantly increased at 24 h post-insult in ischemic hippocampus. GCI also led to a significant decrease in the DNA methylation status of intracisternal A-particle (IAP) RT, but had no marked effect upon DNA methylation of long interspersed nucleotide element 1 (L1) RT. In summary, GCI produced marked increases in RT RNA expression and had a differential effect on the DNA methylation status of two RTs in vulnerable hippocampal neurons destined to die. These data suggest that RTs may play an active role in ischemic brain pathology and that these endogenous mutagens and their regulatory elements could be targeted as potential therapeutic targets in this devastating condition. (C) 2013 Elsevier Inc. All rights reserved.