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Background: The effect of different intracanal medicaments on root fracture resistance has not been thoroughly investigated in the short and long term. To assess the effect of calcium hydroxide (CH), CH combined with Chlorhexidine (CHX), double antibiotic paste (DAP), and simvastatin as intracanal medicaments on the fracture resistance of the human root. One hundred and twenty single-rooted mandibular premolars which were extracted for periodontal reasons were collected for this in vitro study., Materials and Methods: This was an in vitro study. All teeth were decoronated. Root canals were prepared by the Pro taper system, and %2.5 NaOCl was used for irrigation. The smear layer was removed using %5.25 NaOCl and 17% ethylenediaminetetraacetic acid each for 3 min. The samples were randomly divided into five groups based on the medicament: (1) CH (2) CH + CHX (3) Simvastatin (4) DAP (5) Control group. All specimens in each group were incubated for 1 week (Subgroup A) and 1 month (Subgroup B). Then, medicaments were removed and filled with gutta-percha and AH26 sealer. All samples were tested for fracture resistance. The data were statistically evaluated with the SPSS software 17. ANOVA and Mann-Whitney U and Wilcoxon tests were used for the analysis of the data. P = 0.05 was considered statistically significant., Results: Although CH and CH + CHX increased the fracture resistance in a 1-week period, there was no significant difference between the groups after 1 month., Conclusion: Under the limitations of this study, CH and CH + CHX, DAP and simvastatin do not have a negative effect on root fracture resistance when used as intracanal medicaments for <1 month., Competing Interests: The authors of this manuscript declare that they have no conflicts of interest, real or perceived, financial or non-financial in this article., (Copyright: © 2022 Dental Research Journal.)