This retrospective study compares the short-term (1 year) and long-term (2 to 5 year) clinical results of regenerative therapy in clinical private practice using a bone allograft for the treatment of intrabony defects in smokers and non-smokers. A total of 110 intrabony lesions were treated with demineralized freeze-dried bone allograft (DFDBA) following thorough defect debridement and root preparation in 53 patients (15 cigarette smokers and 38 non-smokers). Assessments of clinical attachment level (CAL) and probing depth (PD) were recorded at pre-treatment, 1 year post-treatment, and 2 to 5 years post-treatment. At 1 year post-treatment, significant gains in mean CAL were maintained for both smokers (2.7 mm) and non-smokers (3.4 mm). Similarly, significant reductions in mean PD were observed for smokers (3.0 mm) and non-smokers (3.8 mm) at the 1-year follow-up. However, when comparing relative improvements in clinical measures, smokers were found to exhibit significantly poorer treatment results (i.e., sites exhibited less CAL gain) at 1 year and 2 to 5 years follow-up. Relative to pre-treatment scores, differences in improvements observed for CAL at the 1-year evaluation (29.2% for smokers and 42.5% for non-smokers) were sustained in the subgroup of patients at 2 to 5 years follow-up (31.3% for smokers and 41.8% for non-smokers). Similar but non-significant trends were observed for relative reductions in probing depth for smokers and non-smokers at 1 year (41.9% for smokers and 49.3% for non-smokers) and 2 to 5 years follow-up (43.9% for smokers and 48.3% for non-smokers) for the subgroup of patients followed beyond 1 year. These results suggest that smoking adversely affects treatment outcome, as measured by gains in clinical attachment levels of intrabony defects treated by regenerative therapy using DFDBA.