Background Magnetic Resonance Spin TomogrAphy in Time‐domain (MR‐STAT) can reconstruct whole‐brain multi‐parametric quantitative maps (eg, T1, T2) from a 5‐minute MR acquisition. These quantitative maps can be leveraged for synthetization of clinical image contrasts. Purpose The objective was to assess image quality and overall diagnostic accuracy of synthetic MR‐STAT contrasts compared to conventional contrast‐weighted images. Study Type Prospective cross‐sectional clinical trial. Population Fifty participants with a median age of 45 years (range: 21–79 years) consisting of 10 healthy participants and 40 patients with neurological diseases (brain tumor, epilepsy, multiple sclerosis or stroke). Field Strength/Sequence 3T/Conventional contrast‐weighted imaging (T1/T2 weighted, proton density PD weighted, and fluid‐attenuated inversion recovery FLAIR) and a MR‐STAT acquisition (2D Cartesian spoiled gradient echo with varying flip angle preceded by a non‐selective inversion pulse). Assessment Quantitative T1, T2, and PD maps were computed from the MR‐STAT acquisition, from which synthetic contrasts were generated. Three neuroradiologists blinded for image type and disease randomly and independently evaluated synthetic and conventional datasets for image quality and diagnostic accuracy, which was assessed by comparison with the clinically confirmed diagnosis. Statistical Tests Image quality and consequent acceptability for diagnostic use was assessed with a McNemar's test (one‐sided α = 0.025). Wilcoxon signed rank test with a one‐sided α = 0.025 and a margin of Δ = 0.5 on the 5‐level Likert scale was used to assess non‐inferiority. Results All data sets were similar in acceptability for diagnostic use (≥3 Likert‐scale) between techniques (T1w:P = 0.105, PDw:P = 1.000, FLAIR:P = 0.564). However, only the synthetic MR‐STAT T2 weighted images were significantly non‐inferior to their conventional counterpart; all other synthetic datasets were inferior (T1w:P = 0.260, PDw:P = 1.000, FLAIR:P = 1.000). Moreover, true positive/negative rates were similar between techniques (conventional: 88%, MR‐STAT: 84%). Data Conclusion MR‐STAT is a quantitative technique that may provide radiologists with clinically useful synthetic contrast images within substantially reduced scan time. Evidence Level: 1 Technical Efficacy: Stage 2