Background Postoperative cognitive dysfunction (POCD) is a significant cause of morbidity after noncardiac surgery. Identified risk factors are largely limited to demographic characteristics. We hypothesized that POCD was associated with Apolipoprotein E4 (APOE4) genotype and plasma biomarkers of brain injury and inflammation. Methods 394 patients over age 55 undergoing major elective noncardiac surgery were enrolled in this prospective observational study. Apolipoprotein E genotyping was performed at baseline. Plasma was collected at baseline, end of surgery, 4.5, 24, and 48-h postoperatively. Six protein biomarkers were assayed (B-type natriuretic peptide, C-reactive protein, D-dimer, matrix metalloproteinase-9, neuron specific enolase, S-100B). Neurocognitive testing was conducted at baseline, 6 weeks, and 1 yr after surgery; scores were subjected to factor analysis. The association of APOE4 and biomarkers with POCD was tested using multivariable regression modeling. Results 350 patients (89%) completed 6-week neurocognitive testing. POCD occurred in 54.3% of participants at 6 weeks and 46.1% at 1 yr. There was no difference in POCD between patients with or without the APOE4 allele (56.6 vs. 52.6%; p = 0.58). The continuous cognitive change score (mean ± SD) was similar between groups (APOE4: 0.05 ± 0.27 vs. non-APOE4: 0.07 ± 0.28; p = 0.53). 291 subjects (74%) completed testing at 1 yr. POCD occurred in 45.9% of APOE4 subjects versus 46.3% of non-APOE4 subjects (p = 0.95). The cognitive score was again similar (APOE4: 0.08 ± 0.27 vs. non-APOE4: 0.05 ± 0.25; p = 0.39). Biomarker levels were not associated with APOE4 genotype or cognition at 6 weeks or 1 yr. Conclusion Cognitive decline after major noncardiac surgery is not associated with APOE4 genotype or plasma biomarker levels.