Microvascular dysfunctions are associated with poor prognosis in sepsis. However, the potential role of clinical assessment of peripheral ischemic microvascular reserve (PIMR), a parameter that characterizes the variation of peripheral perfusion index (PPI) after brief ischemia of the upper arm, as a tool to detect sepsis-induced microvascular dysfunction and for prognostic enrichment has not been established. To address this gap, this study investigated the association of high PIMR with mortality over time in patients with sepsis and its subgroups (with and without shock) and peripheral perfusion (capillary-refill time). This observational cohort study enrolled consecutive septic patients in four Intensive-care units. After fluid resuscitation, PIMR was evaluated using the oximetry-derived PPI and post-occlusive reactive hyperemia for two consecutive days in septic patients. Two hundred and twenty-six patients were included-117 (52%) in the low PIMR group and 109 (48%) in the high PIMR group. The study revealed differences in mortality between groups on the first day, which was higher in the high PIMR group (RR 1.25; 95% CI 1.00-1.55; p = 0.04) and maintained its prognostic significance after multivariate adjustment. Subsequently, this analysis was made for sepsis subgroups and showed significant differences in mortality only for the septic-shock subgroup, with was higher in the high PIMR group (RR 2.14; 95% CI 1.49-3.08; p = 0.01). The temporal ΔPPI peak values (%) analyses did not demonstrate maintenance of the predictive value over the first 48 h in either group (p > 0.05). A moderate positive correlation (r = 0.41) between ΔPPI peak (%) and capillary-refill time (s) was found within the first 24 hours of diagnosis (p < 0.001). In conclusion, detecting a high PIMR within 24 h appears to be a prognostic marker for mortality in sepsis. Furthermore, its potential as a prognostic enrichment tool seems to occur mainly in septic shock.