The aged brain is characterized by an increase in pro-inflammatory and oxidative molecules (Griffin et al., 2006, Finkel and Holbrook, 2000), with a concomitant decrease in anti-inflammatory and anti-oxidative mediators (Murali and Panneerselvam, 2007) and evidence from this laboratory has suggested that the polyunsaturated fatty acid, eicosapentaenoic acid (EPA) attenuates some of these age-related changes (Lonergan et al., 2004, Lynch et al., 2007). The aim of the present study was to investigate age-related changes in several markers of microglial activation and to establish whether treatment of aged and young rats with EPA or its metabolite docosapentaenoic acid, (DPA), modulated any change which occurred with age. Groups of young (3-5 months) and aged rats (22-24 months) were divided into control and experimental groups; the animals in the experimental group received 200mg/kg/day EPA or DPA orally for 8 weeks. At the end of this period, animals were killed by cervical dislocation and cryostat sections were prepared from hemisected brains and stained for evidence of change in markers of microglial activation, CD11b, MHC class II, and CD68, as well as for expression of activated caspase 3, and the marker of oxidative stress, 8-OHdG. There was a marked increase in expression of each of the markers of microglial activation in sections prepared from aged, compared with young, rats; this is consistent with previous evidence of an age-related increase in microglial activation (Griffin et al., 2006) and, significantly this effect was attenuated in sections prepared from aged rats which received EPA or DPA. Furthermore, the evidence indicated that caspase 3 immunoreactivity was increased with age and that this was also attenuated by EPA and DPA. Consistent with earlier evidence of an increase in oxidative change in tissue prepared from aged rats, we also report that 8-OHdG staining was greater in sections prepared from aged, compared with young, rats and that this effect was markedly reduced in sections prepared from aged rats which received EPA and DPA. This finding is consistent with previous observations which identified an anti-oxidative effect of EPA (Lonergan et al., 2004). These data demonstrate that the EPA derivative, DPA, like EPA itself, possesses anti-oxidative properties and that this is likely to be a consequence of the modulatory effect of the fatty acids on microglial activation.