Non-cirrhotic portal vein thrombosis (ncPVT) most often occurs in the setting of intraabdominal proinflammatory processes. Less often, ncPVT may result from primary hematologic thrombophilia (most commonly JAK2V617F). Although these etiologic categories are pathophysiologically distinct, they are treated similarly using anticoagulation. We conducted a retrospective assessment of outcomes among ncPVT patients harboring JAK2V617F, and compared them to outcomes among patients with other etiologies for ncPVT, to determine whether anticoagulation alone is adequate therapy for JAK2V617F associated PVT. Outcomes were complete radiographic resolution (CRR) of PVT, recanalization (RC) of occlusive PVT, and development of significant portal hypertension (SPH). Three-hundred-thirty ncPVT patients seen between 1/2000 and 1/2019, including 37 harboring JAK2V617F (JAK2), 203 with other evident etiology (OE) for PVT, and 90 with no evident etiology (NE) for PVT followed for a median 29 months (53, 21, and 32 months respectively). Outcomes among the JAK2 cohort were dismal relative to the other groups. CRR rates were 8%, 31%, and 55% for the JAK2, NE, and OE cohorts respectively (multivariable HR JAK2:OE = 0.15 (0.05, 0.49), p = 0.0016). RC rates were 16%, 33%, and 49% for the JAK2, NE, and OE cohorts respectively (multivariable HR for RC JAK2:OE = 0.24 (0.09, 0.63), p = 0.0036). SPH rates were 49%, 32%, and 17% for the JAK2, NE, and OE cohorts respectively (multivariable HR for SPH JAK2:OE = 1.23 (0.62, 2.42), p = 0.5492). Given the strikingly poor outcomes among patients harboring JAK2V617F, anticoagulation alone does not appear to be adequate therapy for this cohort. Further investigation into thrombolysis and/or thrombectomy as an adjunct to anticoagulation is merited in this high-risk group.