The difficulties in communication about sexuality-related matters in HIV prevention require appropriate research approaches. Scenarios can be useful in qualitative, quantitative research methods and interventions related to sensitive cognitive issues of human sexuality. This paper presents an analysis of the use of scenarios in HIV/AIDS prevention research from the literature and empirical evidence. Examples of scenario-based instrument development research studies in safer sex communication for the prevention of HIV/AID by Kalichman (2000) and Magowe (2006) are provided. A computer-based search of articles addressing the use of case scenarios in research was conducted on Google and Google scholar, using the following search terms: “case scenarios”, “scenarios in research”, case scenarios in safer sex negotiation: “case scenarios in safer sex communication”, “case scenarios in dyadic communication”, “partner communication”, “case research”, “vignettes in HIV/AIDS research”, and, “sexuality related vignettes”. Papers included provided the definition, purpose, components, types of scenarios, use of scenarios in safer sex communication. Examples are drawn from instruments development studies using with case scenarios. Twenty-nine documents were retrieved, and eight of these studies addressed the use of scenarios in research. Five studies were specifically on HIV prevention research, focusing on safer sex communication, negotiation or couple/partner communication. The content of the studies included the definition of scenarios, case scenarios and vignettes; purpose and use of scenarios in research. Studies showed that scenarios are useful in qualitative elicitation of themes and content for instrument development for further quantitative research. Nursing deals with sensitive and complex cognitive issues in human behavior, and therefore scenario-based research can help develop personoriented research and interventions while protecting the individual’s privacy and confidentiality.