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Cancer-related fatigue is a prevalent and debilitating condition that persists for years into survivorship. Studies evaluating both fish oil supplementation on fatigue and associations between fish oil consumption and fatigue have shown mixed effects; it is unknown what factors contribute to these differential effects. Herein, we investigate whether the nutritional status of cancer survivors was associated with serum omega-3 concentration or change in serum omega-3s throughout a fish oil supplementation study, and then if any of these factors were associated with fatigue. Breast cancer survivors 4–36 months post-treatment with moderate-severe fatigue were randomized to take 6 g fish oil, 6 g soybean oil, or 3 g of each daily for 6 weeks. Baseline nutritional status was calculated using the Controlling Nutritional Status tool (serum albumin, lymphocytes, cholesterol). At baseline and post-intervention, serum fatty acids were quantified and fatigue was assessed using the Multidimensional Fatigue Symptom Inventory. Participants (n = 85) were 61.2 ± 9.7 years old with a body mass index of 31.9 ± 6.7 kg/m2; 69% had a good nutritional score and 31% had light-moderate malnutrition. Those with good nutritional status had greater total serum omega-3s at baseline (p = 0.013) and a greater increase in serum omega-3s with supplementation (p = 0.003). Among those who were supplemented with fish oil, greater increases in serum omega-3s were associated with greater improvements in fatigue. In conclusion, good nutritional status may increase uptake of fatty acid supplements, increasing their ability to improve fatigue.