Abstract Background Pruritus is a common condition in chronic kidney disease, especially for patients receiving haemodialysis. Chronic kidney disease associated-pruritus (CKD-aP) can be distressing and have a negative impact on quality of life (QoL). This post hoc analysis aimed to assess the relationship between pruritus relief and QoL. Methods Data from phase 3 trials ([NCT03422653, NCT03636269 grouped], and NCT03998163) of the novel antipruritic difelikefalin (N = 914) were used to assess the relationship between reductions in pruritus intensity at Week 12 (24-hour Worst Itching Intensity Numeric Rating Scale; WI-NRS), perceived improvement in itch (Patient Global Impression of Change, PGI-C) and pruritus-related QoL (Skindex-10 questionnaire). Results Patients receiving difelikefalin had greater improvements in Skindex-10 total scores than those receiving placebo (LS mean treatment difference –3.4; 95% CI –5.5, –1.3; P = 0.002) and greater improvements across Skindex-10 domains (disease, mood, and social functioning) at Week 12. In patients receiving difelikefalin, those with clinically meaningful improvements in pruritus (≥3-point reduction in WI-NRS score) at Week 12 had a greater improvement in Skindex-10 total score (mean difference 14.2; 95% CI 11.0, 17.3; P < 0.001) and Skindex-10 domains than those with a < 3-point reduction in WI-NRS score. Improvements in Skindex-10 total scores correlated with PGI-C. Conclusions Improvements in pruritus intensity following 12 weeks’ treatment with difelikefalin were associated with improvements in QoL. Larger improvements in Skindex-10 scores were seen in patients with a greater reduction in pruritus intensity, indicating that improvements in pruritus are associated with a range of factors, such as mood and social functioning, that affect pruritus-related QoL.