Aims/hypothesis: The effect of a foot ulcer on health-related quality of life (HRQoL) of patients with diabetes mellitus and their caregivers is unclear, and was therefore evaluated prospectively in this multicentre study. Methods: HRQoL according to the 36-item health-related quality of life questionnaire (SF-36) of 294 patients (ulcer duration >= 4 weeks) and 153 caregivers was analysed at baseline (time-point zero [T0]), once the ulcer was healed or after 20 weeks (time-point 1 [T1]), and 3 months later (time-point 2 [T2]). Patients with severe ischaemia were excluded. Results: The mean age of the patients was 60 years, 72% were male, and time since diagnosis of diabetes was 17 years. Patients reported a low HRQoL on all SF-36 subscales. At T1, HRQoL scores in physical and social functioning were higher in patients with a healed vs a non-healed ulcer (p < 0.05). At T2, these differences were larger, with higher scores for physical and social functioning, role physical and the physical summary score (all p < 0.05). Within-group analysis revealed that HRQoL improved in different subscales in patients with a healed ulcer and worsened in patients with a persistent ulcer from T0 to T2 (all p < 0.05). The caregivers of patients with a persisting ulcer had more emotional difficulties at T2. Conclusions/interpretation: Diabetic patients with a healed foot ulcer had a higher HRQoL than patients with a persisting ulcer. Healing of a foot ulcer resulted in a marked improvement of several SF-36 subscales 3 months after healing (from T0 to T2). HRQoL declined progressively when the ulcer did not heal. A diabetic foot ulcer appeared to be a large emotional burden on the patients' caregivers, as well.