Introduction: Identification of a potent biomarker related to smoking cessation can play a key role in predicting prognosis and improving treatment outcomes. This study aimed to evaluate the contribution of new biomarkers based on levels of cotinine (Cot) and/or carbon monoxide (CO) to the short- and long-term quit rates of nicotine replacement therapies (nicotine patch (NP) and nicotine lozenge (NL)). Methods: In this prospective interventional study, a sample of 124 smokers under treatment with the 5A's method was selected between April 2016 and December 2018 in an outpatient smoking cessation center in 18th region of Tehran. They were divided into two groups for NP (n = 56) and NL (n = 61) interventions. The levels of Cot and CO were measured using ELISA and breath analysis at the beginning of the study. Three markers were calculated: Cot/CO, Cot to cigarette per day ratio (Cot/CPD), and CO/CPD. To determine the odds of smoking cessation success, binary logistic regression models and generalized estimating equations (GEE) model were analyzed by SPSS software. Results: Of the NP participants, 30.4% and 19.6% were abstinent in 2 and 6 months respectively, while NL was found less effective with 19.7% for 2-month follow-up and 13.1% for 6-month follow-up. The 6-month success of attempts to quit was significantly different for the NP participants at the second half of Cot/CO (P = 0.029). In the NL participants, CO/CPD would be a superior predictor for the success of smoking cessation (P > 0.05). Conclusions: The findings of this study suggested two markers, Cot/CO and CO/CPD in order, for the optimum treatment outcomes of NP and NL.