Background and Purpose— The CT angiography (CTA) spot sign predicts hematoma expansion and poor outcome in patients with primary intracerebral hemorrhage (ICH). The biological underpinnings of the spot sign remain poorly understood; it may be that the underlying vasculopathy influences its presence. Therefore, we conducted a study to identify genetic predictors of the spot sign. Methods— In an ongoing prospective cohort study, we analyzed 371 patients with CTA and genetic data available. CTAs were reviewed for the spot sign by 2 experienced readers, blinded to clinical data, according to validated criteria. Analyses were stratified by ICH location. Results— In multivariate analysis, patients on warfarin were more likely to have a spot sign regardless of ICH location (OR, 3.85; 95% CI, 1.33–11.13 in deep ICH and OR, 2.86; 95% CI, 1.33–6.13 in lobar ICH). Apolipoprotein E ϵ2, but not ϵ4, was associated with the presence of a spot sign in lobar ICH (OR, 2.09; 95% CI, 1.05–4.19). There was no effect for ϵ2 or ϵ4 in deep ICH. Conclusions— Patients with ICH on warfarin are more likely to present with a spot sign regardless of ICH location. Among patients with lobar ICH, those who possess the apolipoprotein E ϵ2 allele are more likely to have a spot sign. Given the established relationship between apolipoprotein E ϵ2 and vasculopathic changes in cerebral amyloid angiopathy, our findings suggest that both hemostatic factors and vessel pathology influence spot sign presence.