Background: Whole brain radiotherapy (WBRT) has historically been a standard of care in patients with multiple brain metastases. Studies show WBRT may be associated with a transient detriment in hematological parameters because of exposure to a larger proportion of circulating lymphocytes, platelets and hematopoietic cells within the bone marrow of the cranium. We tested the hypothesis that stereotactic radiotherapy (SRS) has reduced hematologic toxicity in patients compared to WBRT. Methods: We retrospectively identified 100 patients treated for brain metastasis, with either SRS or WBRT from 2016 to 2019, and queried their pre- and post-treatment hematological parameters including hemoglobin, total white blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count, and platelet count. CTCAE v5.0 was used for grading hematologic toxicities. Serial values were compared by treatment type and controlled for age, gender, & systemic therapy. Student t-test was used for intergroup comparison and p-value <0.05 was considered significant. Results: Of 100 patients, median brain metastases was 3 (range 1-22), 51 received SRS and 49 received WBRT. We observed that patients treated with WBRT had a significantly higher post-treatment reduction in platelet count (-51.2 vs 9.8; p=0.001) and higher incidence of any grade thrombocytopenia (31.2% vs 10%; p=0.019) compared to patients treated with SRS. We also noted that compared with SRS, WBRT was associated with a higher post-treatment reduction in circulating lymphocytes (-0.80 vs 0.14; p = 0.071) and higher incidence of G3+ lymphopenia (43.2% vs 22.2%; p=0.07). Numerical incidence of any G3+ hematological toxicity was also higher in the WBRT group but the difference was not statistically significant (40% vs 28%, p=0.162). Hemoglobin count, WBC, and ANC were not meaningfully different pre- and post-treatment for either group. Conclusions: WBRT results in an increased amount and duration of radiation exposure to circulating intracranial blood volume. In our study, patients treated with WBRT experienced higher rates of clinically significant lymphopenia & thrombocytopenia compared to patients treated with SRS. In addition to the cognitive benefits of SRS compared to WBRT, there may be significant hematologic benefits as well. Further studies are warranted to clarify and validate these findings.