Lymphatic venous anastomosis is associated with a low incidence of lower extremity lymphoedema-associated cellulitis; however, the exact relationship is unknown. This multicentre RCT evaluated the effect of lymphatic venous anastomosis on prevention of cellulitis. Patients with secondary lower extremity lymphoedema who underwent at least 3 months of non-operative decongestive therapy were assigned randomly to lymphatic venous anastomosis or conservative therapy. The primary and secondary outcomes were cellulitis frequency, and assessments of circumference, hardness, and pain respectively. Overall, 336 patients were divided into two groups: 225 in the full-analysis set (primary outcome 225; secondary outcomes 170) and 156 in the per-protocol set (primary outcome 156; secondary outcomes 110). In both analyses, lymphatic venous anastomosis with non-operative decongestive therapy was more effective in preventing cellulitis than non-operative decongestive therapy alone; the difference between groups in reducing cellulitis frequency over 6 months was −0.35 (95 per cent c.i. −0.62 to −0.09; P = 0.010) in the full-analysis set (FAS) and −0.60 (−0.94 to −0.27; P = 0.001) in the per-protocol set (PPS) Limb circumference and pain were not significantly different, but lymphatic venous anastomosis reduced thigh area hardness (proximal medial and distal and lateral proximal). Four patients experienced contact dermatitis with non-operative decongestive therapy alone. Lymphatic venous anastomosis in combination with non-operative decongestive therapy prevents cellulitis. UMIN00025137, UMIN00031462.