BACKGROUND: Detecting change in health status over time and ascertaining meaningful changes are critical elements when using health-related quality of life (HRQL) instruments to measure patient-centered outcomes. The PedsQL Sickle Cell Disease module, a disease specific HRQL instrument, has previously been shown to be valid and reliable. Our objectives were to determine the longitudinal validity of the PedsQL Sickle Cell Disease module and the change in HRQL that is meaningful to patients. METHODS: An ancillary study was conducted utilizing a multi-center prospective trial design. Children ages 4-21 years with sickle cell disease admitted to the hospital for an acute painful vaso-oclusive crisis were eligible. Children completed HRQL assessments at three time points (in the Emergency Department, one week post-discharge, and at return to baseline (One to three months post-discharge). The primary outcome was change in HRQL score. Both distribution (effect size, standard error of measurement (SEM)) and anchor (global change assessment) based methods were used to determine the longitudinal validity and meaningful change in HRQL. Changes in HRQL meaningful to patients were identified by anchoring the change scores to the patient's perception of global improvement in pain. RESULTS: Moderate effect sizes (0.20-0.80) were determined for all domains except the Communication I and Cognitive Fatigue domains. The value of 1 SEM varied from 3.8-14.6 across all domains. Over 50% of patients improved by at least 1 SEM in Total HRQL score. A HRQL change score of 7-10 in the pain domains represented minimal perceived improvement in HRQL and a HRQL change score of 18 or greater represented moderate to large improvement. CONCLUSIONS: The PedsQL Sickle Cell Disease Module is responsive to changes in HRQL in patients experiencing acute painful vaso-occlusive crises. The study data establish longitudinal validity and meaningful change parameters for the PedsQL Sickle Cell Disease Module. TRIAL REGISTRATION: ClinicalTrials.gov (study identifier: NCT01197417 ). Date of registration: 08/30/2010.