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Introduction The role of primary prophylaxis (PP) with granulocyte colony-stimulating factor (G-CSF) for patients with metastatic pancreatic adenocarcinoma (MPA) treated with FOLFIRINOX is unknown. We aimed to compare the frequencies of grades 3 or 4 neutropenia (G3/4N) and febrile neutropenia (FN) and survival outcomes according to the use of PP. Methods This is a retrospective study. We included patients with pathologically confirmed MPA treated with FOLFIRINOX in first-line. Patients who received primary prophylaxis (PP group) were compared to patients who received secondary or no G-CSF (no-PP group). Overall survival (OS) and progression-free survival (PFS) were evaluated using the standard Cox proportional hazard model. To account for potential biases, we performed sensitivity analyses excluding patients who received secondary prophilaxis and treating G-CSF as a time-dependent covariate in extended Cox proportional hazard models. Results The study population consisted of 123 patients. PP was used by 75 patients (61.0%). G3/4 N occurred more frequently among patients without PP (10.7 vs 41.7%; P < .001). There was no difference in the frequency of FN between groups (5.3 vs 8.3%; P = .710). In multivariate analysis, PP was associated with a trend toward improved OS (HR = .66; 95% confidence interval [95% CI] .41 - 1.07; P = .094). In the multivariate model excluding patients with secondary prophylaxis (HR = .54; 95% CI 0.32 - .91; P = .022) and in the time-dependent model (HR = .47; 95% CI 0.28 - .80; P = .005), PP was associated with statistically superior OS. Conclusions Despite the reduction in the frequency of G3/4N, the risk of FN among patients treated with FOLFIRINOX without G-CSF is too low to justify its use in a routine basis. However, given the potential of G-CSF to improve survival in this setting, further studies are warranted to assess its role during treatment with FOLFIRINOX for patients with MPA.