In this report, we analyze trends in interleukin-6 (IL-6) production in people living with human immunodeficiency virus (PLWH), as a function of smoking behaviors and race, using a clinic-based case-control design. Peripheral blood mononuclear cells (PBMCs) were collected from a multiethnic cohort of 120 PLWH to measure IL-6 in culture supernatant. The data indicated that stimulated PBMC produced significantly higher levels of IL-6 in smokers than nonsmokers. However, as expected, this relationship was substantially modified by race. The distinctive production of IL-6 across different racial groups highlights the need for additional studies and suggests that African American smokers have enhanced production of IL-6 than other groups. Additional analyses indicate that higher IL-6 levels are related to the predicted use of mentholated cigarettes, which are more frequently used by African Americans. These findings warrant further investigation and indicate the critical need for tailored preventive interventions.