Background Prophylaxis with granulocyte colony-stimulating factors (G-CSFs) reduce the severity and duration of chemotherapy-induced neutropenia. Currently, the use of G-CSF prophylactic treatment to prevent neutropenia and its complications varies widely in clinical practice with no standardization for intermediate-risk chemotherapy regimens. Objective: The purpose of this study was to assess neutropenic outcomes in patients receiving intermediate-risk chemotherapy regimens who receive primary versus secondary prophylactic G-CSFs. Methods: This is a retrospective, multicenter cohort study of patients who received intermediate risk chemotherapy regimens and at least one dose of G-CSF therapy. 121 patients were included and were divided into primary (n = 76) or secondary prophylaxis (n = 45) groups. The primary outcome for this study was the incidence of neutropenic episodes per course of treatment. The secondary outcomes included the percentage of patients who experienced delays in chemotherapy doses, the number of chemotherapy dose reductions, and the number of subsequent treatment delays. Results: The incidence of neutropenic episodes over the course of therapy was 0.42 episodes in the primary group compared to 1.52 episodes in the secondary group (p < 0.05). 10.5% of patients in the primary group versus 54.3% of patients in the secondary group experienced chemotherapy dose delays (p < 0.05). There were no statistically significant differences in chemotherapy dose reductions or in the average number of FN risk factors between groups. Conclusion: This retrospective, cohort study determined that patients receiving intermediate risk chemotherapy regimens should receive primary prophylaxis, regardless of risk factors in order to decrease episodes of neutropenia and chemotherapy dose delays.