Purpose <p>Chronic hematological malignancies progress slowly, potentially manifesting symptoms spanning months to years. HM-PRO is developed as a comprehensive clinical tool for assessing symptoms in hematology. The aim was to investigate the effect of a nurse-led systematic approach to symptom identification and management using HM-PRO in outpatient care in patients with chronic hematological malignancies.</p> Methods <p>This is a randomized trial including 94 patients to investigate an intervention comprising (1) HM-PRO data collection, (2) HM-PRO assessment guided by an algorithm, and (3) nurse-led tailored symptom management. The control arm received standard follow-up care. The primary outcome was change in QoL. Secondary outcomes were change in prevalence of physical and psychological symptoms.</p> Results <p>A statistically significant difference in QoL change scores over time favored the intervention (diff. 10.3; <i>p</i> = .04). For secondary endpoints, a significant between group difference in change over time for severity scores was observed in fatigue (diff. − 13.6; <i>p</i> = .003), overall symptom burden (diff. − 0.7 points; <i>p</i> = .029), emotional functioning (diff. 10.0; <i>p</i> &lt; .0001), and anxiety (diff. − 2.5; <i>p</i> = .001).</p> Conclusion <p>A 12-month nurse-led symptom management intervention within hematology significantly improved QoL, emotional functioning, fatigue, anxiety, and overall symptom burden over time. This is the first randomized trial investigating nurse-led clinical application of the HM-PRO questionnaire providing knowledge on the efficacy of systematic symptom management in clinical practice. This study highlights both the pivotal role of nurses and multidisciplinary support and the inherent value of tailored symptom management.</p> Trial registration <p>Clinical trial registration number: NCT04757545 (02/12/2021).</p>