The objective of this study was to evaluate the prognostic value of C-reactive protein (CRP), procalcitonin (PCT), and their combination for mortality in patients with septic shock. This multicenter, prospective, observational study was conducted between November 2015 and December 2017. A total of 1,772 septic shock patients were included, and the overall 28-day mortality was 20.7%. Although both CRP and PCT were elevated in the non-survivor group, only CRP had statistical significance (11.9 mg/dL vs. 14.7 mg/dL, p = 0.003, 6.4 ng/mL vs. 8.2 ng/mL, p = 0.508). Multivariate analysis showed that CRP and PCT were not independent prognostic markers. In the subgroup analysis of the CRP and PCT combination matrix using their optimal cut-off values (CRP 14.0 mg/dL, PCT 17.0 ng/dL), both CRP and PCT elevated showed significantly higher mortality (Odds ratio 1.552 [95% Confidence intervals 1.184–2.035]) than both CRP and PCT not elevated (p = 0.001) and only PCT elevated (p = 0.007). However, both CRP and PCT elevated was also not an independent predictor in multivariate analysis. Initial levels of CRP and PCT alone and their combinations in septic shock patients had a limitation to predict 28-day mortality. Future research is needed to determine new biomarkers for early prognostication in patients with septic shock.