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Background 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. Objectives 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. Methods 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. Results 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. Conclusions 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. Trial registration number This trial was registered at clinicaltrials.gov as NCT04632810.