This study compared a two-layer (Coban 2 Layer) and a four-layer (Profore) compression bandage system in venous leg ulcer patients. Participants (n = 81) were enrolled into an 8-week, randomised, open-label, ten-centre, crossover clinical trial. The primary endpoint was bandage slippage measured at each dressing change. Secondary endpoints included wound healing, health-related quality of life (HRQoL) and patient preference. Mean slippage estimated from a mixed analysis of variance model (697 visits) was 2.48 cm for the two-layer system and 4.17 cm for the four-layer system (P < 0.001). There were no significant differences in percent of wounds that healed (Fisher's exact test, P = 0.30), in wound area reduction (Wilcoxon rank-sum test, P = 0.88) or in linear healing rate (Wilcoxon rank-sum test, P = 0.94). The HRQoL Physical Symptoms and Daily Living scores were significantly higher with the two-layer system (pooled two-sample t-test, P < 0.05). Patients had a strong preference for the two-layer system (72%) than the four-layer system (22%), with 6% having no preference. In conclusion, the two-layer system exhibited significantly less bandage slippage than the four-layer system. While less bandage slippage did not appear to impact wound healing, there was indication that it may have influenced patient preference in favour of the two-layer system and potentially impacted patients' HRQoL.