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Background: Duroplasty has been widely used in cranial surgery when primary closure is not possible. The goal is to protect the cerebrum and thereby ensure that complications were as few as possible. We reviewed a single-institution experience with a variety of dural substitutes in craniotomy and analyzed the risk factors for duroplasty-associated hemorrhagic complications. Patients and Methods: Patients who received dural replacement after craniotomy or craniectomy between July 2004 and June 2009 were enrolled into this study. Medical records were reviewed for diagnosis, procedure, and type of dural replacement. Clinical courses were reviewed for hemorrhagic complications, including subdural hematoma, extradural hematoma, and subarachnoid hemorrhage. Logistic regression models were used to analyzed the risk factors of duroplasty-associated hemorrhagic complications. Results: Two hundred and twelve patients were included in the study. Overall, the hemorrhagic complication rate was 4.7% (10 patients). Complications were seen for microporous polyester urethane, expanded polytetrafluoroethylene monolayer, polyester silicone, and Biomesh in 4.1%, 0%, and 38.5% of patients, respectively. Patients who received duroplasty with Biomesh had a higher hemorrhagic complication rate with the odds ratio of 24.75 (95% confidence interval, 4.33–141.41) in comparison of those with microporous polyester urethane group after adjusting for individual confounders. Conclusion: The increased risk of hemorrhagic complications associated with craniotomy is modified by choice of dural replacement. Our results could assist clinicians in their decision-making with respect to the optimal timing for synthetic dural substitutes in patients with tumor infiltration of the patient's dura, severe brain swelling in traumatic brain injury, or a result of shrinkage from exposure and electrocautery.