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Background/Objectives: Cancer-related fatigue is one of the most distressing symptoms complained by neoplastic patients. L-arginine has a positive effect on physical performance in normal individuals, on fatigue in diseases other than cancer and on immune response in cancer patients. Methods: Forty-four cancer patients undergoing medical treatment were treated with oral l-arginine 1.66 g and 500 mg of vitamin C b.i.d. Cancer-related fatigue and health-related quality of life were recorded before treatment and after 15 and 30 days employing a visual analog scale and the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) respectively. Results: Daily oral supplementation with l-arginine and vitamin C ameliorated cancer-related fatigue in a statistically significant manner. Health-related quality of life remained mostly unchanged despite patients had advanced cancer and were administered medical treatments including chemotherapy, immunotherapy and biologics. No effect on appetite preservation was observed but in a small percentage of patients Conclusions: Our exploratory study suggests a positive effect of oral supplementation with l-arginine plus vitamin C on cancer related fatigue without significant worsening of quality of life. Due to the heterogeneity of patients sample further studies are needed including more clinically homogenous groups of patients.