BACKGROUND: Nutritional treatment is one of the most important components of multidisciplinary anti-cancer therapy. Home enteral nutrition is considered as a safe procedure, however, it may be associated with the risk of side effects, such as nausea, vomiting, abdominal pain, and diarrhoea. It is uncertain whether diarrhoea is the result of the enteral formula administration or gut dysbiosis. One of the methods which may be used to alter the composition of gut microbiota is the administration of a probiotic strain. Lactobacillus plantarum 299v ingestion was found to diminish the adverse events of irritable bowel syndrome and Clostridium difficile infection - entities that share the symptoms with enteral nutrition side effects. Therefore, the primary aim of this study is to determine the effect of Lactobacillus plantarum 299v on prevention of weight loss of cancer patients receiving home enteral nutrition. The secondary aims are to evaluate the role of this probiotic strain in the improvement of nutritional status, enteral nutrition tolerance, and patients' quality of life. METHODS: Forty patients with cancer receiving home enteral nutrition will be enrolled in this clinical trial and randomized to receive one capsule of Lactobacillus plantarum 299v (Sanprobi IBS®) twice a day or placebo for 12 weeks in a double-blind manner. Laboratory tests (the level of albumin, total protein, transferrin, and total lymphocyte count), anthropometric parameters (body mass, the content of fat mass, muscle mass, and total body water), Nutritional Risk Screening (NRS 2002), enteral nutrition tolerance as well as quality of life will be measured. Measurements will be obtained at the baseline and after 4 and 12 weeks of treatment. DISCUSSION: The adverse events observed during administration of enteral nutrition have an negative impact on enteral formula tolerance and as a consequence patients' quality of life. The previous studies have demonstrated that probiotics may reduce the gastrointestinal symptoms related to enteral nutrition. Thus, administration of Lactobacillus plantarum 299v may be effective in improvement of nutritional status, enteral nutrition tolerance, and quality of life of cancer patients receiving home enteral nutrition. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03940768 .