This study aimed to investigate the clinical feasibility of synthetic magnetic resonance imaging (MRI) with fast imaging protocol for automated brain tissue and myelin volumetry in healthy volunteers at 3.0-T MRI.Thirty-four healthy volunteers were scanned using synthetic MRI with 3 sets of scan parameters: groups Fast (FAS; 2 minutes, 29 seconds), Routine (ROU; 4 minutes, 7 seconds), and Research (RES; 7 minutes, 46 seconds). White matter (WM), gray matter (GM), cerebrospinal fluid (CSF), non-WM/GM/CSF (NoN), brain parenchymal volume (BPV), intracranial volume (ICV), and myelin volume (MYV) were compared between 3 groups. Linear correlation analysis was performed for measured volumes of groups FAS and ROU versus group RES.Significant differences were found in all the measured brain tissue volumes between groups FAS and ROU (P < 0.001), FAS and RES (P < 0.05), and ROU and RES (P < 0.05), except for NoN between groups ROU and RES (P = 0.0673), ICV between groups FAS and ROU (P = 0.2552), and ICV between groups FAS and RES (P = 0.4898). The intergroup coefficients of variation were 4.36% for WM, 6.39% for GM, 10.14% for CSF, 67.5% for NoN, 1.21% for BPV, 0.08% for ICV, and 5.88% for MYV. Strong linear correlation was demonstrated for WM, GM, CSF, BPV, ICV, and MYV (R = 0.9230-1.131) between FAS versus RES, and ROU versus RES.Using synthetic MRI with fast imaging protocol can change the measured brain tissue volumes of volunteers. It is necessary to use consistent acquisition protocols for comparing or following up cases quantitatively.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.