Aims Maintaining quality of life (QoL) in patients with cancer has gathered significant interest, but little is known about its major determinants. We sought to identify determinants of QoL in patients undergoing cancer treatment as well as in treatment‐naïve patients about to commence such therapy. Methods and results QoL was assessed in 283 patients with cancer using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 questionnaire. All patients underwent a battery of tests including physical examination, resting electrocardiogram, hand grip strength, and biochemistry assessment. Using multivariable logistic regression, we found that age [odds ratio (OR) 0.954, 95% confidence interval (CI) 0.916–0.994], resting heart rate (OR 1.036, 95% CI 1.004–1.068), hand grip strength (OR 0.932, 95% CI 0.878–0.990), and the presence of cachexia (OR 4.334, 95% CI 1.767–10.631) and dyspnoea (OR 3.725, 95% CI 1.540–9.010; all P < 0.05) remained independently predictive of reduced QoL. Conclusions Therefore, it may be reasonable to address circumstances that are affecting muscle mass, body weight, and heart rate to maintaining QoL; however, prospective studies to test these endpoints are required.