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Purpose To determine which optimized image quality metric (IQM) refractions provide the best predicted visual acuity (VA). Methods Autorefraction (AR), habitual refraction (spectacles, n = 23; unaided, n = 7), and dilated wavefront error (WFE) were obtained from 30 subjects with Down syndrome (DS; mean age, 30 years; range, 18–50). For each eye, the resultant metric value for 16 IQMs was calculated after >25000 sphero-cylindrical combinations of refraction were added to the measured WFE to generate residual WFE. The single refraction corresponding to each of the 16 optimized IQMs per eye was selected and used to generate acuity charts. Charts also were created for AR, habitual refraction, and a theoretical zeroing of all lower-order aberrations, and grouped into 10 sets with a clear chart in each set. Dilated controls (five observers per set) read each chart until five letters were missed on a high contrast monitor through a unit magnification telescope with a 3 mm pupil aperture. Average letters lost for the five observers for each chart was used to rank the IQMs for each DS eye. Results Average acuity for the best performing refraction for all DS eyes was within five letters (0.11 ± 0.05 logMAR) of the clear chart acuity. Optimized IQM refractions had ∼3.5 lines mean improvement from the habitual refraction (0.37 ± 0.22 logMAR, P < 0.001). Three metrics (Visual Strehl Ratio [VSX], VSX computed in frequency domain [VSMTF], and standard deviation of intensity values [STD]) identified refractions that were ranked first, or within 0.09 logMAR of first, in >98% of the eyes. Conclusions Optimized IQM refraction is predicted to improve VA in DS eyes based on control observers reading simulated charts. Translational Relevance Refractions identified through optimization of IQM may bypass some of the challenges of current refraction techniques for patients with DS. The optimized refractions are predicted to provide better VA compared to their habitual correction.