Purpose To compare the diagnostic yield and complication rates of electromagnetic navigational bronchoscopic (ENB)-guided and computed tomography (CT)-guided percutaneous tissue sampling of lung nodules. Materials and Methods Retrospectively identified were 149 patients sampled percutaneously with CT guidance and 146 patients who underwent ENB with transbronchial biopsy of a lung lesion between 2013 and 2015. Clinical data, incidence of complications, and nodule pathologic analyses were assessed through electronic medical record review. Lung nodule characteristics were reviewed through direct image analysis. Molecular marker studies and pathologic analyses from surgical excision were reviewed when available. Multiple-variable logistic regression models were built to compare the diagnostic yield and complication rates for each method and for different patient and disease characteristics. Results CT-guided sampling was more likely to be diagnostic than ENB-guided biopsy (86.0% [129 of 150] vs 66.0% [99 of 150], respectively), and this difference remained significant even after adjustments were made for patient and nodule characteristics (P < .001). Age, American Society of Anesthesiologists class, emphysema grade, nodule size, and distance from pleura were not significant predictors of increased diagnostic yield. Intraprocedural time for physicians was significantly lower with CT-guided sampling (P < .001). Similar yield for molecular analyses was noted with the two approaches (ENB-guided sampling, 88.9% [32 of 36]; CT-guided sampling, 82.0% [41 of 50]). The two groups had similar rates of major complications (symptomatic hemorrhage, P > .999; pneumothorax requiring chest tube and/or admission, P = .417). Conclusion CT-guided transthoracic biopsy provided higher diagnostic yield in the assessment of peripheral pulmonary nodules than navigational bronchoscopy with a similar rate of clinically relevant complications. © RSNA, 2017 Online supplemental material is available for this article.