Objective: To evaluate clinically and microbiologically the outcomes following the combined application of InGaAsP diode laser and Er,Cr:YSGG laser for nonsurgical treatment of chronic periodontitis (ChP). Method and materials: Forty-two patients (age 45.31 ± 9.78 years, 22 female, 23 smokers) with ChP were randomly treated with subgingival debridement (SD) by means of ultrasonic and hand instruments (control group, n = 21) or with InGaAsP followed 1 week later by InGaAsP + SD + Er,Cr:YSGG (test group, n = 21). In the test group, a second laser treatment was performed for all residual sites (bleeding sites with probing depth [PD] ≥ 4 mm) 2 months after the first laser therapy. At baseline and 6 months after therapy, periodontal clinical and microbiologic parameters were evaluated. Results: Six months after therapy, statistically significant clinical and microbiologic improvements (PD reduction, clinical attachment level [CAL] gain, quantitative reduction of periopathogens) were observed in both groups compared to baseline. However, the use of InGaAsP followed by SD and the adjunctive use of an Er,Cr:YSGG laser, yielded statistically significantly higher clinical (PD, CAL, bleeding on probing, number of sites with PD ≥ 5 mm, PD ≥ 6 mm, PD ≥ 7 mm) and microbiologic (Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Prevotella intermedia, Peptostreptococcus micros, Fusobacterium nucleatum) improvements (P .05) compared to SD alone. Conclusions: In patients with ChP, the adjunctive use of InGaAsP and Er,Cr:YSGG to SD may additionally improve the clinical and microbiologic parameters obtained with SD alone, thus representing a valuable approach in nonsurgical periodontal therapy. Keywords: chronic periodontitis, diode laser, Er, Cr:YSGG, InGaAsP, laser treatment, nonsurgical periodontal therapy