The present study was performed to evaluate the impact of smoking status on 6-month clinical outcomes of a regenerative procedure based on enamel matrix derivative and deproteinized bovine bone mineral in the treatment of intraosseous defects accessed with buccal single flap approach. A total of 22 defects were selected in smoking (n = 11) and nonsmoking (n = 11) patients. Regenerative treatment resulted in similar clinical attachment level (CAL) gain in both smokers and nonsmokers. A trend toward lower 6-month CAL gain and probing depth reduction was observed in patients smoking 11 to 20 cigarettes per day compared to those smoking 1 to 10 cigarettes per day.