Abstract Background Phosphate binders cause high pill burden for dialysis patients, complicate medication regimens, and have unpleasant taste and large size which may affect patients' quality of life. This study explores the association between phosphate binder pill burden and health‐related quality of life (HRQoL) in dialysis patients. Methods We conducted a cross‐sectional multi‐centre cohort study in 21 Dutch dialysis centres. Phosphate binder pill burden was extracted from electronic patient records. Primary outcome was HRQoL measured with the Short Form 12 physical and mental component summary scores (PCS and MCS). Secondary endpoints were severity of gastro‐intestinal symptoms, itching, dry mouth, and mental health symptoms, measured with the Dialysis Symptom Index. Results Of 388 included patients, aged 62 ± 16 years, 77% underwent haemodialysis. PCS scores were comparable for patients with and without phosphate binders. Patients using 1–3 pills reported lower scores for decreased appetite ( β −0.5; 95%CI −0.9 to −0.2), implying better appetite, than patients without phosphate binders. Patients using 4–6 pills also reported lower scores for decreased appetite ( β −0.5; 95%CI −0.8 to −0.1) and for itching ( β −0.5; 95%CI −0.9 to −0.1). Patients using >6 pills reported lower MCS ( β −2.9; 95%CI −6.2–0.4) and higher scores for feeling nervous ( β 0.6; 95%CI 0.1–1.1) and feeling sad ( β 0.4; 95%CI 0.0–0.9). Conclusion Phosphate binder pill burden is not associated with physical quality of life. A higher pill burden is associated with better appetite and less itching. Patients using >6 pills per day report lower mental quality of life and felt nervous and sad more often.