Lipedema is considered an inflammation-related disease, and low-carbohydrate ketogenic diets may help reduce inflammation. However, no randomized controlled trials have investigated the effect of a low-carbohydrate ketogenic diet on inflammatory markers in females with lipedema. To compare changes in inflammatory and fibrosis-associated markers after a low-energy low-carbohydrate diet (LCD) compared with a low-fat diet in females with lipedema, and to explore potential associations between changes in pain and changes in inflammatory and fibrosis-associated markers. Females with lipedema and obesity were randomly assigned to either an LCD or low-fat diet (both 1200 kcal/d) for 8 weeks. Body composition [fat mass (FM) and fat-free mass] and the plasma concentrations of high-sensitivity C-reactive protein (hsCRP), cytokines, and fibrosis-associated markers were measured pre- and postintervention. A total of 70 females were included (35/group) (mean age: 47.3 ± 10.9 y, BMI: 36.9 ± 4.9 kg/m2). Both groups lost weight and FM (kg and %), with a greater reduction in the LCD group. A reduction in macrophage inflammatory protein-1ß, tumor necrosis factor-α, and hsCRP was seen in the LCD group only, despite no significant differences between groups. No associations were found between changes in pain and changes in cytokines and fibrosis-associated markers. Changes in cytokines and fibrosis-associated markers did not differ between low-energy LCD and low-fat diets in females with lipedema, despite a beneficial profile in the LCD group. Inflammation does not seem to be involved in pain reduction following LCD in this patient group. This trial was registered at clinicaltrials.gov as NCT04632810.