BackgroundPancreatic ductal adenocarcinoma (PDAC) stromal disposition is thought to influence chemotherapy efficacy and increase tissue stiffness, which could be quantified noninvasively via MR elastography (MRE). Current methods cause position‐based errors in pancreas location over time, hampering accuracy. It would be beneficial to have a single breath‐hold acquisition.PurposeTo develop and test a single breath‐hold three‐dimensional MRE technique utilizing prospective undersampling and a compressed sensing reconstruction (CS‐MRE).Study TypeProspective.PopulationA total of 30 healthy volunteers (HV) (31 ± 9 years; 33% male) and five patients with PDAC (69 ± 5 years; 80% male).Field Strength/Sequence3‐T, GRE Ristretto MRE.AssessmentFirst, optimization of multi breath‐hold MRE was done in 10 HV using four combinations of vibration frequency, number of measured wave‐phase offsets, and TE and looking at MRE quality measures in the pancreas head. Second, viscoelastic parameters delineated in the pancreas head or tumor of CS‐MRE were compared against (I) 2D and (II) 3D four breath‐hold acquisitions in HV (N = 20) and PDAC patients. Intrasession repeatability was assessed for CS‐MRE in a subgroup of healthy volunteers (N = 15).Statistical TestsTests include repeated measures analysis of variance (ANOVA), Bland–Altman analysis, and coefficients of variation (CoVs). A P‐value <.05 was considered statistically significant.ResultsOptimization of the four breath‐hold acquisitions resulted in 40 Hz vibration frequency, five wave‐phases, and echo time (TE) = 6.9 msec as the preferred method (4BH‐MRE). CS‐MRE quantitative results did not differ from 4BH‐MRE. Shear wave speed (SWS) and phase angle differed significantly between HV and PDAC patients using 4BH‐MRE or CS‐MRE. The limits of agreement for SWS were [−0.09, 0.10] m/second and the within‐subject CoV was 4.8% for CS‐MRE.Data ConclusionCS‐MRE might allow a single breath‐hold MRE acquisition with comparable SWS and phase angle as 4BH‐MRE, and it may still enable to differentiate between HV and PDAC.Level of Evidence: 2Technical Efficacy Stage: 2