THE AIM OF THIS INVESTIGATION was to evaluate the effect of smoking on the outcome of periodontal therapy. The study consisted of 54 patients who participated in a 4-group parallel-arm clinical trial on the efficacy of three locally delivered antimicrobial systems as adjuncts to scaling and root planing in the treatment of sites with persistent pocketing after a course of scaling and root planing. These groups included scaling and root planing either alone (S) (n = 3), or in conjunction with the application of 25% tetracycline fibers (S&T) (n = 13), 2% minocycline gel (S&Mi) (n = 14), or 25% metronidazole gel (S&Me) (n = 14). In each patient four pockets > 5 mm with bleeding on probing (BOP) and/or suppuration were studied. The number of subjects who smoked was: 8 (61.5%) in the S&T group, 8 (57.1%) in the S&Mi group, 6 (42.9%) in the S&Me group, and 6 (46.2%) in the 8 group. The probing depth, at tachment level and other clinical parameters were assessed at baseline and 6 weeks after treatments. The clinical results of this comparative study have been previously reported. Regardless of the type of treatment, the change in the probing depth (Delta PD) and attachment gain (Delta AL) were greater in non-smoker subjects than smoker subjects. Delta PD was 1.14 mm versus 0.76 mm (P = 0.019), and Delta AL was 0.52 mm versus 0.50 mm at (P = 0.845) for non-smokers and smokers respectively. The analysis of variance using the general linear model (GLM) was used for Delta PD and Delta AL and took into account the variations in the treatments, number of smoker subjects per group, and baseline probing depth. There was a significant interaction between the ''smoking'' and the ''baseline PD.'' Further analysis using linear regression indicated that, while there was a significant relationship between the baseline PD and the Delta PD or Delta AL among the non-smokers, weak and insignificant relationship existed among the smoker subjects. Thus, smoking may have an important role in determining the prognosis of periodontal treatment, particularly in persistent and deep pockets.