Background and Purpose— Hematoma volume is the most potent predictor of outcome in spontaneous intracerebral hemorrhage (ICH), and hematoma expansion after hospital presentation occurs in up to 40% of individuals. Among patients with lobar ICH, the apolipoprotein E (APOE) ϵ2 allele predicts larger hematoma volumes at presentation. We investigated whether the ϵ2 allele also identifies individuals at increased risk of hematoma expansion. Methods— We analyzed 510 patients with primary ICH and genetic data available from an ongoing prospective cohort study. Baseline and follow-up CT scans were assessed for ICH location and volume using computer-assisted volumetric methods. Results— Individuals with lobar ICH who possessed APOE ϵ2 were at increased risk for hematoma expansion (OR, 2.72; 95% CI, 1.19–6.23; P =0.009). The highest odds of expansion were in patients who qualified for the diagnosis of cerebral amyloid angiopathy-related ICH and carried the APOE ϵ2 allele (OR, 6.02; 95% CI, 1.60–22.58; P =0.008). There was no effect of ϵ2 on hematoma expansion in deep ICH and APOE ϵ4 had no effect on hematoma expansion in lobar or deep ICH. Conclusions— Possession of APOE ϵ2 predisposes individuals with lobar ICH to hematoma expansion. This effect is even more pronounced in patients with amyloid angiopathy-related ICH, consistent with the ϵ2 allele's role in vascular amyloid deposition and vessel fragility.