The aim of the study was to evaluate the responsiveness of the Short Form Health Survey, the EuroQol 5 Dimension questionnaire, and the Charing Cross Venous Ulcer Questionnaire (CXVUQ) to venous ulcer healing. Participants had health-related quality of life measured at baseline and 12 weeks. Standardized response means were calculated to assess the responsiveness of the instruments to change in an ulcer state (healed vs. unhealed). Three hundred and sixty-eight participants completed the questionnaires at baseline and 360 at 12 weeks. One hundred and ninety-three participants (54%) had healed at 12 weeks. The standardized response means ranged from -0.01 to 0.47 for Short Form Health Survey, 0.10-0.31 for EuroQol 5 Dimension questionnaire, and -0.21 to -0.92 for CXVUQ. Differences between healed and unhealed participants at 12 weeks were significantly different for three of the eight domains on Short Form Health Survey and on all domains for the CXVUQ. There were no significant differences between the groups on the EuroQol 5 Dimension questionnaire scales. CXVUQ was more responsive than the generic instruments to change in ulcer status over 12 weeks for measuring health-related quality of life of patients with venous ulceration.