The present study aims to evaluate compliance of cancer patients to EPA-enriched supplementation at the beginning of chemotherapy, and its effects on inflammation. Gastrointestinal and lung cancer patients were randomly assigned to receive nutritional supplement enriched with 2.2 g EPA or standard isocaloric one. Supplements were introduced 72 h before the first chemotherapy and continued for 4 wk. Serum C-reactive protein was measured and its variation was analyzed according to tumor location and treatment group. Compliance was assessed by phone contact and counting of supplement bottles returned after treatment. Sixty-nine patients were assessed, mean aged 65.5 yr old, most of them (59%) men. Gastrointestinal cancer was more prevalent and lung cancer had the highest C-reactive protein values (P = 0.009). Twenty-four patients interrupted treatment (trend for more interruption in EPA group), mainly because of gastrointestinal intolerance. No difference was found in C-reactive protein variation between EPA and control groups after treatment. Lung tumors showed higher inflammation than gastrointestinal ones. A short intervention with EPA was insufficient to reduce inflammation, which may be caused by the frequent abandoning of treatment. The beginning of chemotherapy may not be the optimal time point to initiate EPA supplementation because uncomfortable effects of both treatments may lead to poor adherence.