Background Signal contamination from long T2 water is a major challenge in direct imaging of myelin with MRI. Nulling of the unwanted long T2 signals can be achieved with an inversion recovery (IR) preparation pulse to null long T2 white matter within the brain. The remaining ultrashort T2 signal from myelin can be detected with an ultrashort echo time (UTE) sequence. Purpose To develop patient-specific whole-brain myelin imaging with a three-dimensional double-echo sliding inversion recovery (DESIRE) UTE sequence. Materials and Methods The DESIRE UTE sequence generates a series of IR images with different inversion times during a single scan. The optimal inversion time for nulling long T2 signal is determined by finding minimal signal on the second echo. Myelin images are generated by subtracting the second echo image from the first UTE image. To validate this method, a prospective study was performed in phantoms, cadaveric brain specimens, healthy volunteers, and patients with multiple sclerosis (MS). A total of 20 healthy volunteers (mean age, 40 years ± 13 [standard deviation], 10 women) and 20 patients with MS (mean age, 58 years ± 8; 15 women) who underwent MRI between November 2017 and February 2019 were prospectively included. Analysis of variance was performed to evaluate the signal difference between MS lesions and normal-appearing white matter in patients with MS. Results High signal intensity and corresponding T2* and T1 of the extracted myelin vesicles provided evidence for direct imaging of ultrashort-T2 myelin protons using the UTE sequence. Gadobenate dimeglumine phantoms with a wide range of T1 values were selectively suppressed with DESIRE UTE. In the ex vivo brain study of MS lesions, signal loss was observed in MS lesions and was conformed with histologic analysis. In the human study, there was a significant reduction in normalized signal intensity in MS lesions compared with that in normal-appearing white matter (0.19 ± 0.10 vs 0.76 ± 0.11, respectively; P < .001). Conclusion The double-echo sliding inversion recovery ultrashort echo time sequence can generate whole-brain myelin images specifically with a clinical 3-T scanner. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Port in this issue.