BACKGROUND: Syphilis, together with other sexually transmitted infections, remains a global public health problem that is far from being controlled. People deprived of liberty are one of the vulnerable population. Control activities in prisons rely mostly on passive case detection, despite the existence of affordable alternatives that would allow switching to active case-finding strategies. Our objective was to develop a mathematical modelling framework for cost-effectiveness evaluation, from a health system perspective, of different approaches using rapid tests for the detection of syphilis in inmates' populations and to explore the results based on a Chilean male prison population. Methods: A compartmental model was developed to characterize the transmission dynamics of syphilis inside a prison with the ongoing strategy (passive case detection, with VRDL + FTA-ABS), considering the entrance and exit of inmates over a 40 year period. The model allows simulation of the implementation of a reverse algorithm for the current situation (rapid test + VDRL), different screening strategies (entry point, massive periodically; both with rapid test + VDRL) and treatment of detected cases. The parameters for the exploratory exercise were obtained from systematic searches of indexed and grey literature and field work (EQ-5D questionnaire application and key actors interviews). Probabilistic sensitivity analysis was conducted to account for uncertainty in relevant parameters. RESULTS: The proposed framework allows the evaluation of different detection strategies. In this study, all the strategies were cost-effective in the baseline scenario when considering an ICER threshold of 1 Chilean GDP per capita (US$15,000). The strategies most likely to be cost-effective (over 80% probability) were: current situation with reverse algorithm, entry point screening and mass screening every two years; the latter was the most effective, achieving the lowest prevalence (0.7% and 1.7% over the period versus the 3% prevalence in the current situation).CONCLUSIONS: Mathematical modelling that considers the performance of different tests and detection strategies could be a useful tool for decision making. The exploratory results show the efficiency of adopting both the use of the rapid tests and performing active case detection to significantly reduce the burden of syphilis in Chilean prisons in the near future.