Objective This study examined the short‐term and long‐term effects of using a screening instrument on psychological distress and health‐related quality of life (HRQoL) among cancer patients receiving radiotherapy. In addition, we investigated the effect of early psychosocial treatment on patients' overall health‐related outcomes as previous research showed that patients in the screening condition were referred to a psychosocial caregiver at an earlier stage. Methods A cluster randomised controlled trial with a randomisation at the levels of 14 radiotherapists, 568 patients was conducted. Patients were asked to complete questionnaires at 3 and 12 months follow‐up. Results Mixed models analyses showed no significant intervention effects on patients' overall extent of psychosocial distress and HRQoL, both on the short and long terms. Post‐hoc analyses revealed significant interactions of the intervention with early referral and improved HRQoL and anxiety, suggesting that earlier referral might influence short‐term HRQoL and experienced anxiety in patients. Conclusions Our results suggest that the use of a psychosocial screening instrument among patients receiving radiotherapy in itself does not sufficiently improve patients' health‐related outcome. The effective delivery of psychosocial care depends upon several components such as identification of distress and successful implementation of screening procedures. One of the challenges is to get insight in the effects of early referral of cancer patients for psychosocial support because early referral might have a favourable effect on some of the patients' health‐related outcomes. Copyright © 2013 John Wiley & Sons, Ltd.