Background: Therapy with elastic compression stockings has been the cornerstone for prevention of post-thrombotic syndrome for decades in patients after acute deep venous thrombosis. It is uncertain who benefits most from therapy, and what the optimum duration of therapy should be. We therefore aimed to assess the safety and efficacy of individualised duration of compression therapy versus the standard duration of 24 months following an initial treatment period of 6 months. Methods: We did a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial at 12 hospitals in the Netherlands and two in Italy. We randomly assigned patients (1:1) with acute proximal deep vein thrombosis of the leg and without pre-existent venous insufficiency (Clinical Etiological Anatomical and Pathophysiological score <C3) to receive either individualised duration of elastic compression therapy or standard duration of therapy for 24 months following an initial treatment period of 6 months. Randomisation was done with a web-based automatic randomisation programme (TENALEA) and a random block size (2-12), and was stratified by centre, age, and body-mass index. In the initial phase, compression was applied within 24 h of diagnosis according to three prespecified protocols. All patients received elastic compression stockings (30-40 mm Hg) for 6 months, and were instructed to wear them every day during ambulant hours. Thereafter treatment was tailored on the basis of clinical signs and symptoms scored according to the Villalta post-thrombotic syndrome scale; patients assigned to individualised therapy with two consecutive Villalta scores of 4 or less were instructed to stop using the stockings. Patients were followed up for 2 years and assessed at five clinic visits at study inclusion, and 3, 6, 12, and 24 months after diagnosis (stocking allocation was not revealed to the assessors). The primary outcome was the proportion of patients with post-thrombotic syndrome at 24 months diagnosed according to original Villalta criteria (a score of ≥5 on two consecutive occasions at least 3 months apart) assessed by intention to treat. The predefined non-inferiority margin for the difference in success rates was set at 7·5%. This study has been completed and is registered with ClinicalTrials.gov, number NCT01429714. Findings: Between March 22, 2011, and July 1, 2015, we enrolled 865 patients and randomly assigned 437 to individualised duration compression stockings and 428 to standard duration. 283 (66%) of 432 patients in the intervention group were advised before 24 months to stop wearing elastic compression stockings (236 [55%] of 432 patients after 6 months, and 47 [11%] of 432 at 12 months). Post-thrombotic syndrome occurred in 125 (29%) of 432 patients receiving individualised duration of therapy and in 118 (28%) of 424 receiving standard duration of therapy (odds ratio for difference 1·06, 95% CI 0·78 to 1·44). The absolute difference was 1·1% (95% CI -5·2 to 7·3), thus meeting the non-inferiority margin. 24 patients died, 17 (4%) in the individualised treatment group and seven (2%) in the standard duration group, but no deaths were related to treatment. No serious adverse events related to the intervention occurred. Interpretation: Individualised therapy with elastic compression stockings for the prevention of post-thrombotic syndrome was non-inferior to standard duration of therapy of 24 months. Individualising the duration is effective and could shorten the length of therapy needed, potentially enhancing patients' wellbeing. Funding: ZonMw (Netherlands).