Mecapegfilgrastim has been previously validated for efficacy and safety in neutropenia prevention during clinical trials. This nationwide, real-world study (RWS) evaluates its role in protecting against moderate to severe chemotherapy-induced neutropenia (CIN) in Chinese patients with non-myeloid malignancies.In this prospective study conducted in the 46 centers across China, the patients with non-myeloid malignancies were enrolled, and received subcutaneous injections of mecapegfilgrastim 24 h after each chemotherapy cycle. Outcomes were monitored over four subsequent chemotherapy cycles. The primary outcome was safety, while secondary outcomes included the incidence of grade 3 or higher neutropenia, grade 4 neutropenia, and febrile neutropenia (FN), etc. RESULTS: From June 2019 to March 2022, 2,859 patients were enrolled, contributing to 7,763 observed chemotherapy cycles. Treatment-related adverse events (TRAEs) were noted in 329 patients (11.5%), with white blood cell count increased being the most common (3.6%). The incidence of grade 3 or higher TRAEs was 1.0%. In the first cycle, 236 (8.3%), 125 (4.4%) and 24 patients (0.8%) reported grade ≥ 3 neutropenia, grade 4 neutropenia, and FN, respectively. Across all cycles, the rates of grade ≥ 3 neutropenia, grade 4 neutropenia and FN were 5.8%, 2.7%, and 0.3%, respectively. Notably, primary prophylaxis was associated with lower incidences of grade ≥ 3 neutropenia (7.9%) and grade 4 neutropenia (4.1%) in the first cycle compared to secondary prophylaxis (11.2% and 6.7%, respectively).This RWS reinforces the safety and effectiveness of mecapegfilgrastim in preventing moderate to severe CIN among the patients with non-myeloid malignancies, with primary prophylaxis showing a lower incidence of neutropenia.© 2025. The Author(s).