Granulocyte-colony stimulating factor (G-CSF) is widely acknowledged for its efficacy in managing chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN), albeit accompanied by a spectrum of potential adverse effects. This study conducted a comprehensive analysis utilizing real-world data sourced from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, spanning the years 2004 to 2023, to assess and compare adverse events (AEs) associated with recombinant human G-CSF (rhG-CSF) and its polyethylene glycol-modified form (PEG-rhG-CSF). The analysis revealed a significant increase in the incidence of AEs, with PEG-rhG-CSF implicated in 76,155 cases and rhG-CSF in 10,953 cases. A gender-based disparity was evident, with female patients experiencing a higher incidence of AEs compared to male patients. Specifically, the incidence rates for PEG-rhG-CSF and rhG-CSF in females were 54.2% and 46.1%, respectively, versus 27.1% and 34.7% in males. Bone pain emerged as the most prevalent AE, with PEG-rhG-CSF and rhG-CSF accounting for 2,473 and 581 cases, respectively. Reporting odds ratio (ROR) analysis indicated a higher incidence of bone pain with PEG-rhG-CSF compared to rhG-CSF, with an ROR of 1.17 (95% CI: 1.07-1.29). Furthermore, the study highlighted significant differences in the time to onset of AEs between the two treatments. The median time to onset of AEs was 3 days (IQR: 1-9; p<0.05) for PEG-rhG-CSF, in contrast to 9 days (IQR: 2-42) for rhG-CSF. Notably, the emergence of splenomegaly, capillary leak syndrome, interstitial lung disease, and lung infiltration exhibited delayed intervals, underscoring the imperative for meticulous patient follow-up, particularly given the potential for patient discharge prior to the manifestation of these delayed AEs. Further assessment of real-world data is warranted.