Retrosigmoid craniotomy for microvascular decompression (MVD) has been traditionally performed via craniectomy. Various closure techniques have been described, yet factors associated with wound-related complications remain undetermined. Accordingly, herein, we sought to identify risk factors associated with wound-related complications after such procedures. An institutional retrospective case-control study was performed; outcomes of interest were cerebrospinal fluid (CSF) leak, wound dehiscence, wound infection, and pseudomeningocele. Univariate analysis was performed using Wilcoxon rank sum test for non-parametric continuous outcomes and chi-square test for categorical outcomes. Multivariate logistic regression was performed on binomial outcome variables. The study population included 197 patients who underwent MVD for trigeminal neuralgia (83.2%), hemifacial spasm (12.2%), vestibular nerve section (3.0%), and glossopharyngeal neuralgia (1.5%). The overall wound-related complication rate was 14.2% (n = 28), including twelve patients (6.1%) with CSF leak, ten patients (5.1%) with wound infection, ten patients (5.1%) with pseudomeningocele, and nine (4.6%) patients with wound dehiscence. Using multivariate logistic regression, preoperative anemia and current tobacco use were associated with significantly higher rates of complications (OR 6.01 and 4.58, respectively; p < 0.05), including CSF leak (OR 12.83 and 12.40, respectively, p < 0.05). Of note, use of synthetic bone substitute for cranioplasty was associated with a significantly lower rate of complications (OR 0.13, p < 0.01). Preoperative anemia and current tobacco use significantly increased, while synthetic bone substitute cranioplasty significantly decreased, odds of wound-related complications, the need for treatment, and CSF leaks. Additionally, higher BMI, longer operative duration, and prior radiosurgery may increase risk for wound-related complications.