Objectives The aim of this prospective study was to compare the healing of periapical bone between smokers and nonsmokers after root canal therapy. The effects of duration and intensity of smoking on the healing rate of apical periodontitis were analyzed. Materials and Methods Fifty-five smokers were included in this study. The control group consisted of healthy nonsmokers who matched the smoker group in age and sex. Only teeth with a favorable periodontal prognosis and adequate coronal restoration were included in the study. The periapical status of treated teeth was assessed using the periapical index system at follow-ups after 6 and 12 months. Statistical Analysis The chi-squared test and Mann–Whitney U test were used to assess the changes in periapical index score at baseline and in subsequent time intervals between the two groups examining dichotomized and ordinal data, respectively. Multivariate logistic regression analysis was used to test the association of independent variables age, gender, tooth type, arch type, and smoking index with the outcome variable. The outcome variable was set as the presence versus absence of apical periodontitis. Results The analysis at 12-month follow-up revealed a significantly higher healing rate in control group than in smokers (90.9 vs. 58.2 ; χ2 = 13.846 ; p < 0.001). Smokers had significantly higher periapical index scores than the control group (p = 0.024). The multivariate logistic regression analysis demonstrated that an increase in the value of the smoking index significantly increases the risk of apical periodontitis persistence (odds ratio [OR] =7.66 ; 95% confidence interval [CI]: 2.51–23.28 ; p < 0.001) for smoking index < 400 and (OR = 9.65 ; 95% CI: 1.45–64.14 ; p = 0.019) for smoking index 400 to 799. Conclusion The results from this study show a lower rate of apical periodontitis healing in a group of smokers at 1-year follow-up. Delayed periapical healing seems to be associated with the cigarette smoking exposure.