Background: Peripheral perfusion index (PPI), measured via plethysmography using a pulse oximeter, provides noninvasive, continuous insights into peripheral circulation. This study evaluates PPI's potential as a predictive marker for fluid responsiveness in critically ill patients, aiming to reduce vasopressor use. Methods: A 20-month prospective study was conducted in the multidisciplinary surgical ICU of Christian Medical College, Vellore. Patients meeting specific inclusion criteria were enrolled. Parameters including blood pressure, pulse pressure (PP), heart rate, left ventricular outflow tract velocity time integral (LVOT VTI), oxygen saturation, and PPI were recorded before and after a passive leg raise (PLR) test. Positive PLR responders received fluid resuscitation, and PPI changes were monitored at regular intervals. The study excluded patients with peripheral vascular disease, burns involving extremities, those on nitroglycerin or other vasodilator infusions, and those on high doses of vasopressors. Results: A 39% increase in PPI was identified as the threshold for fluid responsiveness. Subgroup analysis revealed variability: trauma patients showed a 55% increase, obstetrics patients 41%, and postoperative patients 6%. Notably, the study found that spontaneous breathing and minimal vasopressor requirements enhanced the reliability of PPI as a fluid responsiveness marker. Conclusion: Peripheral perfusion index is a reliable and practical tool for predicting fluid responsiveness in spontaneously breathing critically ill patients. It offers a noninvasive and dynamic method to guide volume resuscitation, particularly when combined with established hemodynamic markers such as LVOT VTI and PP changes. This study underscores the importance of using PPI in conjunction with other parameters for comprehensive fluid management. Further validation in larger and more diverse patient populations is warranted to confirm these findings and optimize resuscitation strategies.