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<b></b> <i>Background:</i> Data on volume changes after complex decongestive therapy (CDT) for leg lymphedema are sparse. This naturalistic prospective cohort study aimed to quantify the intraindividual changes of leg volume after comprehensive inpatient rehabilitation, focusing on intensive CDT, and to relate these changes to health-related quality of life (HRQOL). <i>Patients and methods:</i> Limb volume of patients with leg lymphedema (n = 101; 75 women) were measured between entry and discharge (3 weeks later) by the 4 cm measurement method according to Kuhnke and the Perometer® method. Changes were also expressed as standardised response means (SRM). The change on the Freiburg Quality of Life Assessment for lymphatic disorders, short version (FLQA-lk) total score was predicted using multivariate linear regression analysis with volume data adjusted for various confounders. <i>Results:</i> The overall mean volume decrease on the 4 cm/Perometer® method for both legs combined was 1.94/1.31 l for all patients, corresponding to SRMs of 1.04/0.86. In the lymphedema-affected limbs, the decreases ranged between 1.03 and 1.40 l/0.77 and 0.99 l (SRMs 0.70-1.72/0.67-1.28). The total volume loss (4 cm) of both legs of all n = 101 patients correlated by 0.240 (bivariate, p = .010) and by 0.216 (multivariate, adjusted, p = .045). <i>Conclusions</i>: After multidisciplinary rehabilitation focusing on intensive CDT, moderate to large effects on reducing limb volume were observed. Volume reduction was positively associated with improvement in HRQOL.