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Introduction: Fibrinolytic therapy for spontaneous intraventricular hemorrhage (IVH) appears to reduce mortality with uncertain benefit on long-term functional outcomes. Threshold for volume of IVH which responds to intraventricular fibrinolytic therapy with therapeutic benefit has not been determined.Methods: CLEAR III, a randomized, multi-center, double-blinded, placebo-controlled trial was conducted to determine if pragmatically employed external ventricular drainage (EVD) plus intraventricular Alteplase improved outcome, in comparison to EVD plus saline. We analyzed of IVH volume strata from study randomization: Large IVH: volume ≥50 mL; small IVH: volume<20 mL. We assessed clinical variables and outcomes by IVH volume group. Outcome measures were blinded assessment of modified Rankin score (mRS) at 30, 180 and 365 days, (with mRS>3 signifying poor outcome). We performed logistic regression to evaluate outcomes by IVH volume group.Results: Among the 500 patients enrolled, 55 (11%) had IVH volumes >50 mL and 222 (44.4%) had IVH volume <20mL. Subjects with large volume IVH were older (mean, 62.3 vs. 58.1 years; p=0.01), had smaller ICH volume (6.1 vs. 9.9 mL; p<0.001), less thalamic ICH (16.4% vs. 63.6%; p<0.001), more pre-admission use of anticoagulants and antiplatelet agents and greater proportion of high intracranial pressure readings during monitoring at all thresholds (>20, 30, 40 mmHg), compared to those with IVH volume <50mL. Day 180 mortality and poor mRS were 49.1% and 81.8% in large volume IVH compared to 13.1% and 43.3% in small volume IVH. In logistic regression models adjusted for confounders, drainage of >85% IVH volume was significantly associated with higher odds of good outcome (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.3) and lower odds of mortality (OR, 0.3; 95% CI, 0.1-0.8) compared to <85% drainage, in patients with baseline volumes <50mL. Removal of >85% IVH volume (n=3/55) was not associated with improved outcomes in patients with large IVH.Conclusions: IVH volume >50mL may represent a cohort without identified benefit from fibrinolytic treatment. Defining an upper limit for IVH volume would benefit from a larger sample and other methods of achieving IVH reduction.