OBJECTIVES: Smoking is an established risk factor in many pathologies of the cardiovascular system. The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) trial affords an in-depth evaluation into the effect of smoking on patients with chronic limb threatening ischemia (CLTI). BEST-CLI's prospective, randomized design evaluated outcomes in patients suitable for both open or endovascular intervention and randomized patients between endovascular intervention (ENDO) versus open surgical bypass (OPEN). The outcomes are reported stratified by smoking status. METHODS: In the BEST-CLI trial, patients were stratified by current smokers (CS) and non-smokers (NS), which included both previous smokers or never smokers. Endpoints at 4 years include the primary trial outcomes (major adverse limb events [MALE] or all-cause death), as well as above ankle amputation, all cause death, major or minor reintervention, major adverse cardiac events (MACE), MALE, and MALE or peri-operative death (MALE-POD). Multivariable Cox regression models were created with NS serving as the reference group. RESULTS: Patients received bypass using single segment saphenous vein (SSGSV) (n=621), bypass using alternative conduits (n=236) or endovascular procedures (n=923). There were 641 current smokers and 1,137 nonsmokers. In the combined cohort of patients receiving ENDO or OPEN, CS status was associated with a higher rate of MALE [HR 1.27 (1.05,1.55), p=0.02] but a lower rate of all-cause death [HR 0.80 (0.66,0.97), p=0.02] when compared to NS. In the OPEN group, CS had a lower rate of all-cause death [HR 0.74 (0.56,0.98), p=0.04] than NS and no significant difference in MALE [HR 1.18 (0.85,1.63), p=0.34]. In the ENDO group, CS had a higher rate of above ankle amputation [HR 1.51 (1.04,2.19), p=0.03] and MALE [HR 1.33 (1.04,1.69), p=0.02]. Additionally, on subset analysis of the entire cohort it was found that when comparing prior smokers to never smokers there was a 24% increase in reintervention (p=0.05) and when comparing current smokers to never smokers there was a 27% increase in reintervention (p=0.04). CONCLUSION: Current smokers had worse limb outcomes in the BEST-CLI trial. Current smokers undergoing endovascular revascularization had higher rates of MALE and above ankle amputations following adjustment. Current smoking did not impact MALE in patients with CLTI undergoing open surgical bypass.