Rationale: Data about the influence of the type of sedation on yield, complications, and tolerance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are based mostly on retrospective studies and are largely inconsistent.Objectives: To determine whether the type of sedation influences the diagnostic yield of EBUS-TBNA, its complication rates, and patient tolerance.Methods: Patients referred for EBUS-TBNA were randomized (1:1) to undergo this procedure under general anesthesia (GA) or moderate sedation (MS). Pathologists were blinded to group allocation.Measurements and Main Results: The main outcome was "diagnostic yield," defined as the percentage of patients for whom EBUS-TBNA rendered a specific diagnosis. One hundred and fortynine patients underwent EBUS-TBNA, 75 under GA and 74 under MS. Demographic and baseline clinical characteristics were well balanced. Two hundred and thirty-six lymph nodes (LNs) and six masses were sampled in the GA group (average, 3.2 6 1.9 sites/ patient), and 200 LNs and six masses in the MS group (average, 2.8 6 1.5 sites/patient) (P = 0.199). The diagnostic yield was 70.7% (53 of 75) and 68.9% (51 of 74) for the GA group and MS group, respectively (P = 0.816). The sensitivity was 98.2% in the GA group (confidence interval, 97-100%) and 98.1% in the MS group (confidence interval, 97-100%) (P = 0.979). EBUS was completed in all patients in the GA group, and in 69 patients (93.3%) in the MS group (P = 0.028). There were no major complications or escalation of care in either group. Minor complications were more common in the MS group (29.6 vs. 5.3%) (P , 0.001). Most patients stated they "definitely would" undergo this procedure again in both groups (P = 0.355).Conclusions: EBUS-TBNA performed under MS results in comparable diagnostic yield, rate of major complications, and patient tolerance as under GA. Future prospective multicenter studies are required to corroborate our findings. Clinical trial registered with www.clinicaltrials.gov (NCT 01430962).