Patients with recurrent ovarian cancer (ROC) 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. The study aimed to look at the co-occurrence of symptoms within MOST symptom indexes and the relationship between MOST symptom indexes and important determinants of 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. Both the pre-treatment and post-treatment information were analyzed. Co-occurrence symptom groups were identified using exploratory factor analysis and hierarchical cluster analysis. Relationships between MOST symptom indices and HRQL were analyzed using path models. Analyzed were the responses of 762 women at baseline and 681 at treatment’s completion who had filled out all 22 symptom-specific MOST items and at least 1 HRQL measure. At the outset and conclusion of treatment, 4 groups of symptoms emerged: gastrointestinal symptoms, peripheral neuropathy symptoms, nausea and vomiting, and psychological symptoms. At both time points, psychological symptoms (MOST-Psych) and symptoms related to illness (ovarian cancer) or treatment (MOST-DorT) were associated with lower QLQ-C30 and OV28 functioning domain scores and worse overall health. Across all analyses and time periods, four clusters of MOST symptoms persisted. These results point to MOST as a promising intervention for increasing HRQL, particularly when combined with suitable symptom management referral pathways for use in clinical practice.