The aim of our study was to develop a Spanish-structured HIV risk of exposure and indicator conditions (RE&IC) questionnaire. People attending to an emergency room or to a primary clinical care center were offered to participate in a prospective, 1 arm, open label study, in which all enrolled patients filled out our developed questionnaire and were HIV tested. Questionnaire accuracy, feasibility, and reliability were evaluated.Valid paired 5329 HIV RE&IC questionnaire and rapid HIV tests were performed, 69.3% in the primary clinical care center, 49.6% women, median age 37 years old, 74.9% Spaniards, 20.1% Latin-Americans. Confirmed hidden HIV infection was detected in 4.1%, while HIV RE&IC questionnaire was positive in 51.2%. HIV RE&IC questionnaire sensitivity was 100% to predict HIV infection, with a 100% negative predictive value. When considered separately, RE or IC items sensitivity decreases to 86.4% or 91%, and similarly their negative predictive value to 99.9% for both of them. The majority of people studied, 90.8% self-completed HIV RE&IC questionnaire. Median time to complete was 3 minutes. Overall HIV RE&IC questionnaire test-retest Kappa agreement was 0.82 (almost perfect), likewise for IC items 0.89, while for RE items was lower 0.78 (substantial).A feasible and reliable Spanish HIV RE&IC self questionnaire accurately discriminated all non-HIV-infected people without missing any HIV diagnoses, in a low prevalence HIV infection area. The best accuracy and reliability were obtained when combining HIV RE&IC items.