Objective: Emerging evidence suggests that chest radiography (CXR) following central venous catheter (CVC) placement is unnecessary when point-of-care ultrasound (POCUS) is used to confirm catheter position and exclude pneumothorax. However, few providers have adopted this practice, and it is unknown what contributing factors may play a role in this lack of adoption, such as ultrasound experience. The objective of this study was to evaluate the diagnostic accuracy of POCUS to confirm CVC position and exclude a pneumothorax after brief education and training of nonexperts. Methods: We performed a prospective cohort study in a single academic medical center to determine the diagnostic characteristics of a POCUS-guided CVC confirmation protocol after brief training performed by POCUS nonexperts. POCUS nonexperts (emergency medicine senior residents and critical care fellows) independently performed a POCUS-guided CVC confirmation protocol after a 30-minute didactic training. The primary outcome was the diagnostic accuracy of the POCUS-guided CVC confirmation protocol for malposition and pneumothorax detection. Secondary outcomes were efficiency and feasibility of adequate image acquisition, adjudicated by POCUS experts. Results: Twenty-six POCUS nonexperts collected data on 190 patients in the final analysis. There were five (2.5%) CVC malpositions and six (3%) pneumothoraxes on CXR. The positive likelihood ratios of POCUS for malposition detection and pneumothorax were 12.33 (95% confidence interval [CI] = 3.26 to 46.69) and 3.41 (95% CI = 0.51 to 22.76), respectively. The accuracy of POCUS for pneumothorax detection compared to CXR was 0.93 (95% CI = 0.88 to 0.96) and the sensitivity was 0.17 (95% CI = 0.00 to 0.64). The median (interquartile range) time for CVC confirmation was lower for POCUS (9 minutes [8.5–9.5 minutes]) compared to CXR (29 minutes [1–269 minutes]; Mann-Whitney U, p < 0.01). Adequate protocol image acquisition was achieved in 76% of the patients. Conclusion: Thirty-minute training of POCUS in nonexperts demonstrates adequate diagnostic accuracy, efficiency, and feasibility of POCUS-guided CVC position confirmation, but not exclusion of pneumothorax.