Fever is a common symptom in cancer patients. The most frequent causes of fever are infections, malignancy itself, various medications, transfusions, and allergy. Although it is necessary to treat the cause of fever, if possible, symptomatic fever management is also important. Surprisingly, little attention is paid to this topic in the medical literature, despite the fact that it is a very frequent problem. In order to support symptomatic fever therapy, we wanted to study the patients' discomfort accompanying fever and the beneficial effects of the symptomatic fever management. To the best of our knowledge, there is an absence of studies in this area, despite the fever discomfort can be an important reason for the antipyretic treatment, mainly in cancer patients. In this non-randomized open label pilot study, three intravenous antipyretics were tested in five groups of patients: diclofenac (75 mg, brief intravenous [IV] infusion) vs. metamizol (2500 mg or 1000 mg, brief IV infusion) vs. propacetamol (2000 mg or 1000 mg, slow IV injection or brief IV infusion). The study included 254 febrile episodes mainly in hemato-oncological patients with axillary temperature at least 38 degrees C. The main study endpoints were: changes in axillary temperature, improvement in patient comfort, and number and nature of adverse events. To support justification for symptomatic fever management in febrile patients, we asked the first 45 study subjects to fill in a questionnaire concerning their opinions about fever, fever-associated discomfort, and relief upon antipyretic therapy. All study medications had a significant antipyretic effect. However, metamizol at the dose 2500 mg was considered as the most effective, while propacetamol at the dose 1000 mg showed the lowest antipyretic efficacy. Concerning tolerability and adverse events, there were significant differences among the treatment groups. Diclofenac and metamizol (both 2500 mg and 1000 mg) were tolerated at best. All tested antipyretics significantly improved comfort in febrile patients. Overall, 87% of patients declared improvement in their comfort after administration of antipyretics. Based on the results of the present study, the choice of the antipyretic drug should depend on the clinical status of patient, contraindications, and potential adverse events and risks of the selected agent. It is advisable to use proparacetamol at the higher dosage and to administer it as a brief IV infusion in order to avoid injection-related adverse events. The symptomatic antipyretic treatment in febrile cancer patients is supported by patients themselves and has a significant role in the complex supportive care. Discomfort of patients during fever episodes may be greater than previously thought.