Background: This pilot, double-blind, comparator-controlled trial evaluated the safety and tolerability of an oral targeted medical nutrition (TMN) supplement for the management of cachexia in patients with non-small-cell lung cancer (NSCLC). Methods: Patients receiving first-line chemotherapy for NSCLC with weight loss or low BMI were randomized 1:1 to receive juice-based TMN (∼200 kcal; 10 g whey protein; ≥2.0 g eicosapentaenoic acid/docosahexaenoic acid in fish oil; and 10 μg 25-hydroxy-vitamin D3) or a milk-based isocaloric comparator twice daily for 12 weeks (ClinicalTrials.gov: NCT02515032). Primary endpoints included number/type of adverse events and changes in vital signs/laboratory parameters. Secondary endpoints included measures of clinical relevance. Survival was an exploratory endpoint. Results: The TMN group (n = 26; mean 64.4 years) experienced fewer adverse events (64 vs. 87) than the comparator group (n = 29; mean 66.0 years), including fewer cases of neutropenia (0 vs. 4). Compliance was slightly lower in the TMN (58.5%) vs. comparator group (73.6%). There were no statistically significant between-group differences in efficacy endpoints. Fewer (4 vs. 10) patients who received TMN than comparator had died by 1-year post baseline. Conclusions: TMN was well tolerated. Trends for improved clinical outcomes with TMN identified in this study warrant further investigation.