The security effectiveness based on users' behaviors is becoming a top priority of Health Information System (HIS). In the first step of this study, through the review of previous studies 'Self-efficacy in Information Security' (SEIS) and 'Security Competency' (SCMP) were identified as the important factors to transforming HIS users to the first line of defense in the security. Subsequently, a conceptual model was proposed taking into mentioned factors for HIS security effectiveness. Then, this quantitative study used the structural equation modeling to examine the proposed model based on survey data collected from a sample of 263 HIS users from eight hospitals in Iran. The result shows that SEIS is one of the important factors to cultivate of good end users' behaviors toward HIS security effectiveness. However SCMP appears a feasible alternative to providing SEIS. This study also confirms the mediation effects of SEIS on the relationship between SCMP and HIS security effectiveness. The results of this research paper can be used by HIS and IT managers to implement their information security process more effectively.