Background: One much needed tool to assist with the monitoring and evaluation of Human Immunodeficiency Virus (HIV) prevention programs is to provide a valid instrument to measure protective sexual behavior and related factors. Objectives: The current study aimed to design a valid and reliable instrument to predict the protective sexual behaviors of women at risk of HIV in Iran. Patients and Methods: The current study was a sequential mixed cross-sectional and methodological research. Initially, via a qualitative research, constructs and factors associated with sexual protective behavior of women at risk were identified through 25 indepth interviews. The questionnaire on predictors of protective sexual behaviors in women at risk of HIV (PSPB) was designed based on a qualitative study, and then its qualitative validity, content, and construct validity were evaluated. Exploratory factor analysis was performed and 200 women at risk participated. Results: Seven concepts emerged after exploratory factor analysis of the 48 items. The content validity ratio (CVR) of the questionnaire constructs were 0.55 to 0.76, and content validity index (CVI) structure was 0.86 to 0.95. Cronbach's alpha coefficient for the entire questionnaire was 0.78, and correlation coefficient of the test-retest reliability for the constructs was from 0.73 to 0.89. Conclusions: The current study proved the capability of the predictors of sexual protective behavior in women at risk for HIV questionnaire as a valid and reliable instrument for the Iranian community
