Background In circulatory shock, tissue hypoperfusion leads to adverse outcomes. We hypothesized that peripheral tissue oxygen saturation (StO(2)), measured with near-infrared spectroscopy (NIRS), could provide a non-invasive method for assessing tissue hypoperfusion and predicting pending organ dysfunction and mortality. Methods ASSESS-SHOCK was a prospective, observational study enrolling circulatory shock patients from April 2019 to May 2023 in three intensive care units (ICU). Adult patients fulfilling the criteria for circulatory shock within 24 h of ICU admission were eligible. Patients underwent continuous 48 h StO(2) (INVOS (TM)) monitoring of the knee region. To express the burden of tissue hypoperfusion we calculated mean StO(2) and areas below predefined StO(2) thresholds. The primary outcome, change in Sequential Organ Failure Assessment (SOFA) score, was dichotomized to improvement or non-improvement in SOFA score from enrollment to day 7 or ICU discharge. Death within 7 days was considered as SOFA non-improvement. 90-day mortality was among the secondary outcomes. Results We included 256 patients. Due to several reasons, including the COVID-19 pandemic, the patient sample was not consecutive. The median of 48-h mean StO(2) was 68.3% (interquartile range [IQR] 57.5-74.1) in SOFA-improvers (n = 171), compared to 63.5% (IQR 52.7-70.8, p = 0.020) in non-improvers (n = 85), and 68.7% (IQR 58.2-74.5) in 90-day survivors, versus 60.9% (IQR 49.5-67.1, p < 0.001) in non-survivors. There were no statistically significant differences in the areas below predefined StO(2) thresholds between the SOFA-improvers and non-improvers but all the areas were larger in 90-day non-survivors. The 90-day mortality was 27.0% (n = 69). In multivariable analyses 48-h mean StO(2) was associated with 90-day mortality (Odds ratio [OR] 0.97, 95% confidence interval [CI 95%] 0.94-1.00, p = 0.047) but not with SOFA change. The association with mortality was, however, no longer significant in multivariable analyses after exclusion of the last 6 hours of StO(2) registration in the patients (n = 29) who died during the 48 h registration (OR 0.97, CI 95% 0.94-1.00, p = 0.062). Conclusions Lower peripheral StO(2) was associated with 90-day mortality in critically ill patients with circulatory shock but not with persisting or worsening organ dysfunction. NIRS shows promise as a non-invasive monitor of tissue perfusion in circulatory shock. Trial registration: ClinicalTrials.gov Identifier: NCT03814564, registered 15 January 2019.