In this longitudinal study we investigated the effect of apolipoprotein E (APOE) genotype on the relation between cognitive decline and cerebrospinal fluid (CSF) F2-isoprostanes, the reference marker for oxidative stress. Twenty non-demented subjects, 58 mild cognitive impairment (MCI) patients, and 63 Alzheimer's disease (AD) patients with measurements of CSF F2-isoprostanes at two time points (with a mean interval of 2.0 ± 1.1 years) and known APOE genotype were included. Mean clinical follow-up time was 3.9 ± 2.4 years. For change in F2-isoprostanes over time and associations with Mini-Mental State Examination scores, age- and gender-adjusted linear mixed models were used. Analyses were done for APOE ε4 carriers and non-carriers separately. In APOE ε4 carriers, annual change in F2-isoprostane levels appeared larger than in APOE ε4 non-carriers (β[SE] 2.5[0.5], p < 0.001 versus 1.8[0.5], p < 0.01). In addition, increase in F2-isoprostanes was associated with further cognitive decline in APOE ε4 carriers (p < 0.05), but not in non-carriers (p = 0.28). Our results reiterate the importance of oxidative stress in neurodegeneration, especially in APOE ε4 carrying patients. Future studies should focus on the possibility of increased vulnerability to oxidative damage in APOE ε4 carriers.