Objective: This clinical study evaluated prospectively adverse events immediately following ultrasound-guided foam sclerotherapy (UGFS) for the treatment of lower extremity venous valvular insufficiency. Incidence of side effects associated with carbon dioxide (CO2) foam was compared with a historical control using air-based foam. The literature on the subject was reviewed. Methods: Vital signs were monitored during and immediately after UGFS, and adverse events were recorded for 24 hours following the procedure. The air-based foam group had 49 patients: 44 women and 5 men. The CO2-based foam group had 128 patients: 115 women and 13 men. CEAP class was C2EpAsPr, describing varicose veins, primary etiology, and saphenous reflux. UGFS followed thermal ablation of the great saphenous vein. Foam was prepared using the three-way tap technique to mix gas with 1% polidocanol in a 4:1 ratio. Segments of the great and small saphenous veins and their tributaries were treated with UGFS. Foam volumes injected were 27 +/- 10 (SD) (6-46 range) and 25 +/- 12 (6-57 range) mL for air- and CO2-based foams respectively (P =.39). Incidence of adverse events was compared by chi(2) statistics. Vital signs were compared by paired t test. Results. During the procedure, the average heart rate decreased by less than 5 bpm for both groups (P <.001), and blood pressure decreased by less than 3 turn Hg in the CO2 group (P <.02). Respiratory rate, electrocardiogram, and pulse oxymetry did not change significantly in both air- and CO2-foarn series (P >.05). Visual disturbances were experienced by 3.1% (4/128) and 8.2% (4/49) patients in the CO2 and air groups respectively (P =.15). Respiratory difficulties or circumoral paresthesia each occurred in 0.8% (n = 1) of the CO2 patients. Incidence of chest tightness (3.1% vs 18%), dry cough (1.6% vs 16%), or dizziness (3.1% vs 12%) were significantly lower in the CO2 vs air groups (P <.02). Nausea occurred in 2% and 4% of the CO2 and air-based foam groups (P =.53). Overall, the proportion of patients describing side effects decreased from 39% (19/49) to 11% (14/128) as CO2 replaced air for foam preparation (P <.001). Similar findings were described in the literature of air-based foam but data on the use of physiological gas were rare. Conclusions. Side effects decreased significantly if CO2 rather than air was employed to make the sclerosing foam for chemical ablation of superficial veins of the lower extremity.