Background: Health-related quality of life (HRQoL) is an important patient-reported outcome to assess in patients with prostate cancer (PC). A variety of general and disease-specific measures have been developed, but there is a lack of evidence on performance of the Centers for Disease Control and Prevention (CDC) Healthy Days (HDs) measure in a population with metastatic disease relative to other validated scales. Objective: To report and understand general HRQoL using the HDs instrument in patients with metastatic PC taking novel oral therapies and compare results to validated scales. Methods: Patients currently enrolled in a Medicare Advantage or Prescription Drug plan treated with enzalutamide or abiraterone acetate were eligible for inclusion. Patients undertook a telephone-based survey including 2 HRQoL questionnaires (Short-Form 36, version 2 [SF-36] survey and the CDC HDs measures), the Service Satisfaction with Cancer Care (SCA) instrument, and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). Higher scores indicated higher HRQoL on all surveys, except the HDs scale, where higher numbers indicated lower HRQoL (ie, unhealthy days). Pearson correlations with SF-36 and HDs measures and SCA and FACIT-Fatigue were assessed. Results: 1,745 patients were eligible to participate; 269 completed the survey and were included in the analysis. The mean (standard deviation) age was 74.4 (±7.3) years and 82% were Caucasian. Patients had lower physical HRQoL and a higher number of physically unhealthy days, compared to mental health impacts on both scales. The mean Physical Component Summary (PCS) and Mental Component Summary (MCS) norm-based scores for the SF-36 were 39.9 (±10.6) and 53.4 (±10.4). The mean number of physically and mentally unhealthy days reported in a 30-day period were 9.2 (±11.3) and 3.9 (±7.7), respectively. The unadjusted correlations between scores were all statistically significant (P<.05). Conclusions: The SF-36 and HDs measures both indicated physical health was impacted more than mental health in these patients. The correlations with both HRQoL measures and the other scales were similar in terms of magnitude and significance. This indicates that the HDs instrument may be a useful measure for assessment of general HRQoL in patients with metastatic PC and provides an understanding of general HRQoL in this population that can be utilized to identify opportunities for enhancing patient-centered care.