Background and Purpose— The Fraxiparin in Stroke Study for the treatment of ischemic stroke (FISS-tris) study showed no superiority of low-molecular-weight heparin (LMWH) over aspirin for the primary end point (Barthel Index) in acute ischemic stroke due to large artery occlusive disease. This study aims to evaluate the efficacy of LMWH and aspirin in selected subgroups so as to generate hypotheses for further studies. Methods— The FISS-tris study was a multicenter, randomized trial to investigate the efficacy and safety of LMWH (nadroparin calcium 3800 antifactor Xa IU/0.4 mL subcutaneously twice daily) or aspirin (160 mg once daily) for the treatment of patients with acute ischemic stroke and large artery occlusive disease. The primary outcome was the Barthel Index score dichotomized at 85 6 months poststroke. Exploratory subgroup analysis was performed using different levels of baseline characteristics and the distribution of symptomatic arteries. Results— Compared with aspirin, LMWH improved outcome among older patients >68 years ( P =0.043; OR, 1.86; 95% CI, 1.02–3.41) without ongoing antiplatelet treatment on admission ( P =0.029; OR, 1.85; 95% CI, 1.06–3.21) and with symptomatic posterior circulation arterial disease ( P =0.001; OR, 5.76; 95% CI, 2.00–16.56). Conclusions— Our findings suggest that LMWH may be of benefit in certain subgroups of patients with acute cerebral infarct and large artery occlusive disease. Hence, further investigation of LMWH may be justified in subgroups such as the elderly, nonusers of antiplatelet agents, and patients with posterior circulation stenosis. Clinical Trial Registration— URL: www.strokecenter.org/trials . Unique identifier: registration no. 493.