Introduction: Chronic immune activation is associated with the accelerated progression of HIV to AIDS; however, affordable markers reflecting this have not yet been determined. The percentage of large unstained cells (%LUCs) is a differential count parameter measured by certain routine hematology analyzers and reflects activated lymphocytes and peroxidase-negative cells. We hypothesized that the %LUCs would be increased in HIV infection and would correlate with markers of immune activation [i.e. CD38 expression on CD8+ T cells (%CD38onCD8) and lipopolysaccharide-binding protein (LBP)] and CD4 counts. Methods: In this cross-sectional study, 78 HIV-infected, antiretroviral therapy-naïve adults and 52 uninfected controls were recruited. %CD38onCD8 and CD4 counts were determined by flow cytometry, LBP levels were assessed by immunoassay, and the %LUCs was tested on a Siemens ADVIA 2120. Results: Significant differences were found between the HIV-infected and control groups for %LUCs (95% CI 2.3-2.7 vs. 1.8-2.2, respectively; p = 0.001), as well as for %CD38onCD8, LBP, and CD4 counts. Furthermore, %LUCs correlated directly with %CD38onCD8 and LBP and inversely with CD4 counts. Conclusion: The %LUCs was significantly increased in this untreated, asymptomatic, HIV-infected group and correlated with markers of immune activation and CD4 counts. Therefore, the %LUCs may be of value in identifying HIV-infected patients at risk of accelerated disease progression.