Objective: The objective of this study was to compare the safety, use, and cost profiles of open thoracotomy vs video-assisted thoracoscopic surgery (VATS) for wedge resection in lung cancer performed by thoracic surgeons in the United States. Methods: The Premier database, which contains complete patient billing, hospital cost, and coding histories from >25 million inpatient discharges and >175 million hospital outpatient visits, was used for this analysis. Eligible patients were those who underwent wedge resection by a thoracic surgeon for cancer diagnosis or treatment through open thoracotomy or VATS in 2007 or 2008. Multivariable logistic regression analyses were run for binary outcomes, and ordinary least squares regressions were used for continuous outcomes. All models were adjusted for patient demographics, comorbid conditions, and hospital characteristics. Results: Of 8,228 eligible procedures, 2,051 patients underwent wedge resections by a thoracic surgeon using the open technique (n = 999) or VATS (n = 1,052). Hospital costs remained significantly higher for open wedge resections than for VATS ($17,377 vs $14,795, P = .000). Surgery time was significantly longer for open resections vs VATS (3.16 vs 2.82 h). Length of stay was 6.34 days for open vs 4.44 days for VATS. Adverse events were significant in the multivariable analysis, with an OR of 1.57 (95% CI, 1.29-1.91) in favor of VATS. Conclusions: Although this retrospective database analysis could not address the issue of oncologic outcome equivalence, a clear advantage of VATS over open wedge lung cancer resection was found for both acute clinical outcomes and hospital costs.