Background: Chronic edema is a condition posing a high burden on patients. The primary aim of the study was to assess the health-related quality of life (QoL) of adult patients living with chronic edema. Methods and Results: As part of an international, multicenter, prospective study, we prospectively assessed the health-related QoL of adult patients living with a chronic edema using a disease-specific tool and a generic one. In total, 1094 patients were included, aged 57 years on average. The average EQ-5D and LYMQOL visual analogue scale (VAS) scores were equal to 63.6 (SD = 20.2) and 6.3 (SD = 2.0), respectively. After adjustment, the EQ-5D VAS was explained by LYMQOL VAS (β = 7.85; p < 0.001), age (β = -0.08; p = 0.02), obesity (β = -1.89; p = 0.001), and male gender (β = 3.32; p = 0.002). As for the LYMQOL VAS, it was independently associated with EQ-5D VAS (β = 0.07; p < 0.001), LYMQOL function (β = -0.21; p < 0.001), and LYMQOL mood (β = -0.49; p < 0.001). Conclusion: This study confirms that patients living with a chronic edema experience a poor disease-specific and generic health-related QoL.