Sepsis is characterized by a dysregulated immune response, and hemogram-derived inflammatory indices have emerged as potential complementary biomarkers of disease severity and prognosis. However, their longitudinal behavior and clinical relevance during sepsis remain poorly characterized in people living with HIV (PLWH). This longitudinal retrospective study included PLWH with sepsis and three comparison groups: PLWH with comorbidities, PLWH without comorbidities, and HIV-negative controls. Hemogram-derived inflammatory indices and clinical severity scores were evaluated at sepsis diagnosis and on days 3 and 7. Longitudinal comparisons, correlations, ROC, Kaplan–Meier, and regression analyses were performed. Among the 22 patients with complete serial measurements through day 7, hemogram-derived inflammatory indices exhibited distinct temporal patterns, whereas cross-sectional analyses at days 0, 3, and 7 were influenced by progressively selected survivor subsets. Lower SII was associated with a shorter time from sepsis diagnosis to death. Component-level analyses showed that low SII predominantly reflected thrombocytopenia and reduced circulating neutrophils, with platelet count accounting for a substantial proportion of the time-to-death information captured by SII. Thus, the clinical meaning of SII depends not only on its absolute value but also on the hematological phenotype underlying it. As a low-cost and widely accessible index, SII warrants further evaluation as a complementary marker of hematological vulnerability in PLWH with sepsis.