The introduction of biosimilars and novel delivery devices between 2014 and 2019 may have changed the utilization of granulocyte colony-stimulating factors (G-CSF). To assess utilization trends of G-CSFs for primary prophylaxis of febrile neutropenia (FN) among patients with cancer receiving myelosuppressive chemotherapy with commercial or Medicare insurance. This cross-sectional study assessed G-CSF utilization trends overall and stratified by regimen febrile neutropenia risk level. Associations between patient characteristics and G-CSF use were evaluated. Patients with cancer, including breast, lung, colorectal, esophageal and gastric, pancreatic, prostate, ovarian, and non-Hodgkin lymphomas, initiating myelosuppressive chemotherapy courses were included from the 2014 to 2019 commercial insurance and 2014 to 2018 Medicare fee-for-service claims databases. Data were analyzed from March to June 2021. Year of chemotherapy initiation. The main outcomes were use and trends of G-CSFs for primary prophylaxis, from completion to 3 days after in the first chemotherapy cycle. In total, 86 731 chemotherapy courses (mean [SD] age, 57.7 [11.5] years; 57 838 [66.7%] women and 28 893 [33.3%] men) were identified from 82 410 patients in the commercial insurance database and 32 398 chemotherapy courses (mean [SD] age, 71.8 [8.3] years; 18 468 [57.0%] women and 13 930 [43.0%] men) were identified from 30 279 patients in the Medicare database. Among the commercially insured population, 39 639 patients (45.7%) received G-CSFs, and 12 562 patients (38.8%) received G-CSFs among Medicare insured patients. Overall G-CSF use increased significantly throughout the study period in both populations, from 45.1% (95% CI, 44.4%-45.7%) of patients in 2014 to 47.5% (95% CI, 46.5%-48.5%) of patients in 2019 (P = .001) in the commercially insured population and from 36.0% (95% CI, 34.2%-38.0%) of patients in 2014 to 39.1% (95% CI, 38.1%-40.1%) of patients in 2018 (P < .001) in the Medicare population. The greatest increases in G-CSF use were observed among patients with high FN risk, from 75.0% (95% CI, 74.1%-76.0%) of patients to 83.2% (95% CI, 82.0%-84.2%) of patients (P < .001) among the commercially insured population and 75.3% (95% CI, 71.8%-78.6%) of patients to 86.2% (95% CI, 84.7%-87.6%) of patients (P < .001) among the Medicare population. Use of G-CSFs decreased in the commercially insured population among patients with intermediate FN risk (from 27.5% [95% CI, 26.4%-28.5%] of patients to 20.4% [95% CI, 19.1%-21.7%] of patients; P < .001) or low FN risk (from 19.3% [95% CI, 18.3%-20.4%] of patients to 16.3% [95% CI, 14.7%-18.0%] of patients; P < .001) and remained stable in the Medicare population (intermediate risk: from 26.4% [95% CI, 23.8%-29.2%] of patients to 28.4% [95% CI, 27.0%-29.8%] of patients; P = .35; low risk: from 19.6% [95% CI, 17.0%-22.4%] of patients to 20.9% [95% CI, 19.6%-22.3%] of patients; P = .58). Factors associated with increased odds of G-CSF use included older age (commercial insurance: adjusted odds ratio [aOR], 1.50 [95% CI, 1.41-1.59]; Medicare: aOR, 1.36 [95% CI, 1.08-1.71]), receiving a regimen with high FN risk (commercial insurance: aOR, 16.01 [95% CI, 15.17-16.90]; Medicare: aOR, 17.17 [95% CI, 15.76-18.71]), and history of neutropenia (commercial insurance: 3.90 (3.67-4.15); Medicare: 3.82 (3.50-4.18). This cross-sectional study found that utilization of G-CSFs increased among patients with cancer with high FN risk in both a commercially and Medicare-insured population, but 14% to 17% of patients still did not receive preventive treatment.