OBJECTIVE： To explore an effective method to formulate management-related strategies for off-lable use of drugs by the evidence-based medicine. METHODS： The process of guideline formulation included seven procedures， i.g. establishment of “guidelies” formulation workgroup； investigation and selection of the status quo on off-label drug use； identification of the clinical problems； retrieval and evaluation and comprehensing of evidence； applification of GRADE in evidence quality grading； formation of the recommendations consensus； peer review and result publication. And eventually guidelines were formed based on the steps. This study took off-label use of rheumatoid immunoprotective subjects as a case to explore. RESULTS & CONCLUSIONS： Based on the evidence evaluation system and above 7 steps， the methods and process of guideline formulation on off-label use of rheumatoid immunoprotective subjects that integrated administration， law， clinical medicine， pharmacy  subjects were made .The process of guideline formulation fully reflects multidisciplinary characteristics of the workgroup， the advanced nature of the process， the comprehensiveness of evidence ，the rigor of evidence quality grading， and the normalization of consensus. It provides reference in methodology for establishing a comprehensive evidence-based evaluation and management system of off-label use of drugs for all clinical specialist disease. Therefore， this scientific research results may promote the standardization and legalization of the off-label use of drugs management in China.