BACKGROUND The objective of this study was to examine associations of symptoms with physical and mental health-related quality of life (HRQOL) in patients with colorectal cancer (CRC) and in patients with lung cancer. METHODS Patients with newly diagnosed CRC (n=3040) or lung cancer (n=2297) who were participating in the Cancer Care Outcomes Research and Surveillance Consortium study completed surveys on general HRQOL and symptoms. HRQOL was measured by using physical component summary (PCS) and mental component summary (MCS) scores on the Medical Outcomes Study 12-item short-form heath survey. Nonspecific cancer symptoms were measured using items from the European Organization for Research and Treatment of Cancer core quality-of-life questionnaire. Cancer type-specific modules developed by the European Organization for Research and Treatment of Cancer were used to assess CRC-specific and lung cancer-specific symptoms. For both cancer types, linear regression models that were controlled for demographic and clinical information were used to examine correlations of nonspecific and cancer-specific symptoms with PCS and MCS scores. RESULTS PCS scores for patients with CRC and lung cancer were below the general population norm of 50 (43 and 37, respectively), and MCS scores were at the population norm. For the CRC sample, in the model that included both symptom indices, an increase in nonspecific symptoms was more strongly associated with lower PCS and MCS scores than an increase in CRC-specific symptoms (PCS, standardized coefficient [β]=-0.41 vs -0.09; MCS, β=-0.38 vs -0.08). In a similar model for lung cancer, increases in lung cancer-specific symptoms were more strongly associated with lower PCS scores (β=-0.34 vs -0.20), whereas nonspecific symptoms were more strongly associated with lower MCS scores (β=-0.34 vs -0.14). CONCLUSIONS Symptoms were associated with HRQOL impairments in recently diagnosed patients. Additional supportive care implemented early in cancer care, regardless of cancer stage, may provide symptom relief and improve HRQOL Cancer 2015;121:2831-2839.