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Blisters are common foot injuries during and after prolonged walking. However, the best treatment remains unclear. The aim of the study was to compare the effect of 2 different friction blister treatment regimens, wide area fixation dressing versus adhesive tape.A prospective observational cohort study.The 2015 Nijmegen Four Days Marches in the Netherlands.A total of 2907 participants (45 ± 16 years, 52% men) were included and received 4131 blister treatments.Blisters were treated with either a wide area fixation dressing or adhesive tape.Time of treatment application was our primary outcome. In addition, effectiveness and satisfaction were evaluated in a subgroup (n = 254). During a 1-month follow-up period, blister healing, infection and the need for additional medical treatment were assessed in the subgroup.Time of treatment application was lower (41.5 minutes; SD = 21.6 minutes) in the wide area fixation dressing group compared with the adhesive tape group (43.4 minutes; SD = 25.5 minutes; P = 0.02). Furthermore, the wide area fixation dressing group demonstrated a significantly higher drop-out rate (11.7% vs 4.0%, P = 0.048), delayed blister healing (51.9% vs 35.3%, P = 0.02), and a trend toward lower satisfaction (P = 0.054) when compared with the adhesive tape group.Wide area fixation dressing decreased time of treatment application by 2 minutes (4.5%) when compared with adhesive tape. However, because of lower effectiveness and a trend toward lower satisfaction, we do not recommend the use of wide area fixation dressing over adhesive tape in routine first-aid treatment for friction blisters.