OBJECTIVES:  Disease-specific outcome measures for use in economic evaluations are growing in popularity. Within cancer there are now two preference-based measures, the EORTC-8D and the QLU-C10D. Both map responses from the EORTC QLQ-C30, a questionnaire which measures the quality-of-life of cancer patients. They share some commonalities in the C30 items that they draw from and the analytical approach applied in selecting their item dimensions, but they differ in other areas (the clinical characteristics of the patient group within which they conducted their analysis and the valuation approach). This is the first analysis comparing the two measures in an external dataset. METHODS:  Cancer 2015, a longitudinal prospective population-based cancer genomic cohort, was utilised in the analysis. Both the EQ-5D-3L and the EORTC QLQ-C30 were asked at baseline (diagnosis) and at various follow-up points (3, 6, 12 months). The respective algorithms were applied to generate health state values for the EORTC-8D and the QLU-C10D. Cancer-specific baseline values were evaluated and compared. Quality adjusted life-years (QALYs) were estimated and assessed. Validity, ceiling effects, agreement and sensitivity in the instruments were also evaluated. RESULTS:  Complete case analysis of 1663 patients found that the EORTC-8D and QLU-C10D are highly correlated (0.947), yet the EORTC-8D values at baseline were significantly higher than the QLU-C10D values (0.830 vs 0.736, p<0.001). There is strong agreement between the instruments at baseline (ICC=0.770). EORTC-8D QALY estimates were significantly higher than QLU-C10D QALYs (0.911 vs 0.821, p<0.001). Differences in QALY estimates appear to be sensitive to the site of the cancer. CONCLUSIONS:  It is well known that generic preference-based measures often produce different conclusions, this analysis confirms that disease-specific measures also suffer from the same variability, even when drawn from the same quality-of-life instrument. Further research is required to understand the reasons for the variability, particularly if recommendations for reimbursement change in light of using one instrument over another.