Background: Brain biopsies of superficial cortex are performed for diagnosis of neurological diseases, but preoperative predictors of successful diagnosis and risks are lacking. Objective: We evaluated effectiveness and outcomes of superficial cortical biopsies and determined preoperative predictors of diagnosis, outcomes, morbidities, and mortality. Methods: A single-institution retrospective analysis of 170 patients who underwent open brain biopsies of superficial cortex was performed. Clinical predictors of effectiveness and outcomes were determined using univariate/multivariate analyses and a system for risk-benefit stratification was created and tested. Results: Brain biopsies led to successful diagnosis in 122 of 170 (71.8%) and affected management in 97 of 170 (57.1%) cases. Factors increasing the odds of diagnostic pathology included age older than 45 years (odds ratio [OR]: 2.67, 95% confidence interval [CI]: 1.34-5.27, P,.01), previous cancer diagnosis (OR: 3.64, 95% CI: 1.69-7.85, P,.001), focal (OR: 3.90, 95% CI: 1.91-8.00, P,.001) and enhancing (OR: 5.03, 95% CI: 2.41-10.52, P,.001) lesions on magnetic resonance imaging, biopsy of specific lesions on magnetic resonance imaging (OR: 9.34, 95% CI: 4.29-20.33, P,.001), and use of intraoperative navigation (OR: 6.59, 95% CI: 3.04-14.28, P,.001). Brain biopsies led to symptomatic intracranial hemorrhage, seizures, other significant morbidities, and perioperative mortality in 12.4%, 16.2%, 37.1%, and 8% of cases, respectively. Risk of postoperative intracranial hemorrhage was increased by a history of aspirin use (OR: 2.51, 95% CI: 1.23-5.28, P,.05) and age older than 60 years (OR: 2.66, 95% CI: 1.36-5.18, P,.01). Conclusion: Effectiveness and risk of morbidity/mortality can be estimated preoperatively for patients undergoing open brain biopsies of the superficial cortex. Older age and specific imaging characteristics increase the odds of diagnostic biopsy. Conversely, older age and aspirin use increases the risk of postoperative complications. Copyright © 2013 by the Congress of Neurological Surgeons.