Current guidelines suggest that polycythemia vera (PV) patients maintain a strict hematocrit less than 45%. However, to date, little is known about the relationship between HCT control and PV- related symptom burden. In this study, PV patient data was analyzed from the CYTO PV trial (n=224) and the MPN-SAF study cohort (n=645). No significant differences in symptom burden were seen at the 6 and 12 month follow-up when evaluating prospective hematocrit control in the CYTO PV cohort. Patients in the MPN-SAF cohort with a worst item score of greater than 5/10 on the Myeloproliferative Neoplasm Symptom Total Symptom Score had a significantly lower mean hematocrit (p=.0376). These findings suggest a relationship between traditional aggressive therapy for PV and increased symptom burden with prolonged therapy. Thus, symptom burden should be considered when contemplating the choice of therapy in the second-line setting for PV.