TRANSESOPHAGEAL ECHOCARDIOGRAPHY (TEE) is carried out in various clinical settings, with an increasing importance, and sedation usually is required to perform it. Several sedative agents are available, and the authors aimed to compare the cardiovascular and respiratory safety of the strategies used for sedation in TEE through a systematic review with network meta-analysis (NMA). The MEDLINE, CENTRAL, EMBASE, and PsycInfo databases were searched in December 2020 for randomized clinical trials (RCTs) comparing sedation strategies for patients undergoing TEE. The authors assessed variations in systolic blood pressure (SBP), heart rate (HR), and peripheral oxygen saturation (SpO2), along with the incidences of hypotension, bradycardia, and desaturation. A random-effect meta-analysis was performed. Nine RCTs (N = 881 patients) with 20 active arms (5 dexmedetomidine; 4 propofol; 4 midazolam; 3 midazolam + opioid; 2 ketamine + propofol; 1 midazolam + ondansetron; 1 midazolam + metoclopramide) and 1 placebo arm were included. Dexmedetomidine was associated with decreases in SBP (mean difference [MD] = -18.78 mmHg; 95% CI [-26.27 to -11.28]) and HR (MD = -11.15 beats/min; 95% CI [-16.15 to -6.15]). Dexmedetomidine significantly reduced the HR compared with ketamine + propofol (-16.90 beats/min; 95% CI: -33.21 to -0.58]) and midazolam + opioid (-24.15 beats/min; 95% CI: -42.67 to -5.63). Midazolam was found to reduce SBP (-12.09 mmHg; 95% CI: -20.43 to -3.74) and was shown to reduce SpO2 compared with the placebo (-1.00%; 95% CI -1.74 to -0.26). Based on the NMA, the drugs with a higher likelihood of decreasing both SBP and HR were dexmedetomidine and midazolam. All of the drugs led to a small decrease (only statistically significant for midazolam) in SpO2, with the systematic use of supplemental O2 in some trials. The risks of hypotension, bradycardia, or desaturation were not significantly different among the evaluated drugs.