Patients with recurrent ovarian cancer can evaluate the efficacy and safety of palliative chemotherapy by using the Measure of Ovarian Symptoms and Treatment (MOST) concerns; a validated patient-reported symptom evaluation instrument for recurrent ovarian cancer (ROC). This research aims to determine if there is a correlation between MOST symptom indexes and essential markers of health-related quality of life and if symptoms within MOST symptom indexes tend to cluster together with health-related quality of life (HRQL). At baseline and before each cycle of chemotherapy, a prospective group of women with ROC completed the MOST-T35, EORTC QLQ-C30, and EORTC QLQ-OV28. Data collected at the beginning and end of treatment were analyzed. Groups of co-occurring symptoms were found using exploratory factor analysis and hierarchical cluster analysis. The correlations between MOST symptom indices and HRQL were analyzed using path models. The sample size was calculated by comparing the number of women who completed all 22 symptom-specific MOST items and at least 1 HRQL measure at baseline (762) and at treatment end (681). At the outset and conclusion of treatment, 4 groups of symptoms emerged: gastrointestinal symptoms, peripheral neuropathy symptoms, nausea and vomiting, and psychological symptoms. Poorer scores on the QLQ-C30 and OV28 functioning domains and lower overall health were associated with higher levels of psychological (MOST-Psych) and disease/treatment-related (MOST-DorT) symptoms. Both statistical approaches and periods agreed on 4 clusters of MOST symptoms. These results point to MOST as a promising intervention for enhancing HRQL, particularly when combined with suitable symptom management referral pathways for use in clinical practice.