Background: Lipedema is a subcutaneous adipose tissue disorder mainly affecting women. Its progressive nature often requires high-volume liposuction for efficient pain reduction. However, aspiration volumes of more than 5 L within a single session may lead to a variety of complications. Thus, we examined the effect of high-volume liposuctions on lipedema patients and the incidence of associated complications. Methods: We analyzed perioperative differences in lipedema patients undergoing low- or high-volume liposuctions. Statistical analyses were performed, investigating postoperative complications and the correlation of patients’ BMI, total amount of aspiration, duration of surgery, hospital stay and hemoglobin alterations. Complications were investigated according to the Clavien–Dindo Classification. Patients were divided in two groups based on the volume aspirated at liposuction (low-volume vs. high-volume liposuction). Results: Overall, 121 sessions were investigated. Mean total volume of aspiration was 8227.851 mL ± 3643.891. Mean preoperative hemoglobin levels were 13.646 g/dL ± 1.075 g/dL. Preoperatively, 7.44% of patients were anemic (Hb < 12 g/dL). Mean postoperative hemoglobin was 10.563 g/dL ± 1.230 g/dL. Postoperatively, 90.10% of patients showed Hb levels below 12 g/dL. Hemoglobin loss differed significantly between the two groups (p = 0.001). Significant correlations between pre- (p = 0.015) and postoperative (p < 0.001) hemoglobin levels and pre- (p < 0.001) and postoperative (p < 0.001) anemia with Class II complications were also seen. The total volume of aspiration did not correlate with complication rates (p = 0.176). Conclusions: Complication rates in high-volume liposuctions are hemoglobin-dependent rather than volume-associated. Preoperative anemia was the most influential for the occurrence of postoperative complications. To safely conduct high-volume liposuctions in lipedema patients, adequate patient selection and preoperative patient preparation are imperative.