Objective: The purpose of this study was to compare the clinical efficacy of nonsurgical periodontal treatment with and without Nd:YAG laser (NDL) applications in smoking and nonsmoking patients with moderate chronic periodontitis (CP). Materials and methods: The study population consisted of 52 patients with generalized moderate CP. The study compared the clinical effects of scaling and root planing (SRP) and SRP plus NDL in periodontal pockets measuring between 4 and 6 mm of smoking and nonsmoking patients with CP. The study patients were divided into four groups: Group 1: test teeth in smoker patients (ST; n = 52 teeth); Group 2: placebo teeth in smoker patients (SP; n = 52 teeth); Group 3: test teeth in nonsmoker patients (NST; n = 52 teeth); and Group 4: placebo teeth in nonsmoker patients (NSP; n = 52 teeth). Clinical examinations were performed immediately before SRP (the baseline) as well as 1 month (R1) and 6 months (R2) after treatment. Results: The recovery for pocket depth (PD), gingival index (GI), and gingival crevicular fluid (GCF) volume in the NST group was higher than in both smoker groups (p < 0.05). Additionally, the changes for each of these parameters in the NSP group were higher than for the SP group (p < 0.05) at R1 and R2. SRP plus NDL application versus SRP application alone did not lead to significant differences in any clinical parameters or in GCF volume between the two groups of patients who smoked (p > 0.05), whereas statistically significant differences existed for PD between nonsmoker groups at R1 and R2 (p < 0.05). Conclusions: Our results supported the idea that NDL applications provide additional benefits in the periodontal treatment of smokers.