Background: Human immunodeficiency virus (HIV) infection and opioid use disorder (OUD) often occur as comorbid conditions. Many nurse practitioners are treating these conditions in their practice. Problem: Most advanced practice registered nursing (APRN) students do not encounter a medically complex patient with both HIV infection and OUD during their clinical experiences. Approach: We present an unfolding simulated standardized patient scenario involving both HIV infection and OUD for APRN students. During each of 3 semesters, the students encounter the patient as he presents for a sexually transmitted infection, an OUD relapse, and, finally, new-onset HIV infection. The scenarios become increasingly complex as the students progress in their clinical experiences. Conclusion: This innovative series of scenarios introduces APRN students to complex comorbid patient situations, with many issues to consider.