Background: Noninvasive fat removal is preferred because of decreased downtime and lower perceived risk. It is important to seek new noninvasive fat removal treatments that are both safe and efficacious. Objective: To assess the extent to which carboxytherapy, which is the insufflation of carbon dioxide gas into subcutaneous fat, results in reduction of fat volume. Methods: In this randomized, sham-controlled, split-body study, adults (body mass index, 22-29 kg/m2) were randomized to receive 5 weekly infusions of 1000 cm3 of CO2 to 1 side of the abdomen, and 5 sham treatments to the contralateral side. The primary outcome measures were ultrasound measurement of fat layer thickness and total circumference before and after treatment. Results: A total of 16 participants completed the study. Ultrasound measurement indicated less fat volume on the side treated with carboxytherapy 1 week after the last treatment (P =.011), but the lower fat volume was not maintained at 28 weeks. Total circumference decreased nominally but not significantly at week 5 compared with baseline (P =.0697). Participant body weights did not change over the entire course of the study (P = 1.00). Limitations: Limitations included modest sample size and some sources of error in the measurement of circumference and fat layer. Conclusion: Carboxytherapy provides a transient decrease in subcutaneous fat that may not persist. Treatment is well tolerated.