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Introduction We systematically reviewed the literature regarding short- and long-term safety and tolerability of prophylactic use of Granulocyte-Colony Stimulating Factor (G-CSF) for chemotherapy-related febrile neutropenia (FN). Methods 730 pertinent records published from 1994 to 2020 were identified. Exclusion criteria included no assessment of safety or Quality of life (QOL). Results Among 88 full-texts included, most studies were conducted during or shortly after G-CSF administration. Mild-to-moderate medullary bone pain was the most reported side effect, usually responsive to anti-inflammatory drugs although potentially impactful on daily functioning. Transient leukocytosis, thrombocytopenia and alterations in biochemistry were also commonly reported. Short-term improvements in patient-reported outcomes were observed as a result of reduction of FN and secondary complications. Secondary myeloid neoplasms were the only reported late effect. No studies evaluated the long-term impact on QOL. Conclusions G-CSF seem safe and well-tolerated, although few data are available on long-term impact of use of G-CSF.