<h3>Purpose/Objective(s)</h3> Preventing malnutrition during chemoradiation (CRT) for head and neck cancer (HNC) is crucial for treatment adherence, minimizing treatment-related complications, and maximizing quality of life (QOL). We sought to assess patient-reported QOL outcomes after integrating exclusive liquid meal replacement with Soylent, a novel meal replacement agent, in patients with HNC undergoing CRT. <h3>Materials/Methods</h3> Patients undergoing definitive or adjuvant concurrent CRT for locally advanced HNC enrolled on our single-institution, prospective phase II protocol evaluating nutritional replacement with Soylent. Patients who reached 5% body weight loss during CRT were transitioned to Soylent meal replacement for all nutritional needs. Patients who reached 10% body weight loss were recommended for gastrostomy tube placement. The University of Washington QOL (UW-QOL) and the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) questionnaires were used to assess patient-reported QOL prior to the receipt of CRT (baseline), as well as at 1, 3, 6, 12, and 18 months following conclusion of CRT. Higher scores indicated better QOL for both assessments. Paired t-test or Wilcoxon signed-rank test was applied to assess whether differences between scores at each time point and baseline exist. Multiple testing was addressed via Benjamini-Hochberg procedure with a false discovery rate threshold of 0.2. <h3>Results</h3> Of the 41 patients who completed evaluable QOL surveys, 33/41 (80%) reached the 5% weight loss threshold and 32/33 (97%) were transitioned to Soylent. Subsequently, 11/33 (33%) on Soylent reached the 10% weight loss threshold, but only 1/11 (9%) received a gastrostomy tube. The nadirs for overall and health-related UW-QOL were reached at 1 month and rebounded to exceed baseline by 6 months. The mean overall UW-QOL score was 71 at baseline compared with 62, 69, 77, 73, and 80 at 1, 3, 6, 12, and 18 months, respectively. Comparing individual UW-QOL domains from baseline to 18 months, significant differences were found in only two domains. Saliva scores decreased from 91 to 73 (adjusted <i>P</i> = 0.02) whereas anxiety scores increased from 51 to 81 (adjusted <i>P</i> = 0.11). FACT-H&N survey scores were reduced from 32 at baseline to 20 at 1 month (adjusted <i>P</i> < 0.001) and 26 at 3 months (adjusted <i>P</i> < 0.001), but increased to 29, 30, and 27 at 6, 12, and 18 months, without significant differences as compared to baseline (adjusted <i>P</i> > 0.57 for all). <h3>Conclusion</h3> This study's results reveal encouraging QOL outcomes from exclusive liquid meal replacement with Soylent, which appear potentially comparable with QOL outcomes from contemporary de-escalation trials in HNC pending further direct comparison. Soylent liquid meal replacement with aggressive dietary monitoring appears to be a promising approach for maximizing patient-reported QOL after conventional, concurrent CRT.