The early detection of surgical site infection (SSI) remains an unsolved problem. Inflammatory factors in fluids drained from surgical sites may be a promising tool for predicting SSI. Previous attempts to predict SSI via such factors have not taken baseline concentrations into account. However, this may have comprised predictive efficacy. In the current study, concentrations of C-reactive protein (CRP) and interleukin 6 (IL-6) in fluid samples drained from surgical sites in 20 patients with SSI and 60 matched controls were assessed, and concentrations from day 2 to day 4 were divided by the concentration at day 1 to achieve concentration standardization. There were no significant differences of CRP or IL-6 concentrations at day 1 or day 2 ( p > 0.05), but there were significant differences at day 3 and day 4 ( p < 0.05). The areas under the curve (AUCs) for SSI of standardized concentrations were higher than those of the corresponding absolute concentrations of CRP and IL-6 in fluid drained at days 3 and 4. Standardized concentrations of CRP at day 4 yielded the highest AUC (0.92; 95% confidence interval: 0.84–0.97), with a sensitivity of 90% and specificity of 80% at the best cutoff. Concentration standardization may improve the efficacy of predicting SSI via CRP and IL-6 in fluids drained from surgical sites. Although the sample size was small, the study demonstrated the feasibility of non-invasive, accurate, and early detection of postoperative SSI in a diverse real population. Further studies are needed to validate the results of the present study and investigate their broader applicability. Impact statement The ability to predict surgical site infections (SSIs) early would be advantageous. Previous studies have investigated the use of inflammatory factors in fluids drained from surgical sites to predict SSI, but the diagnostic efficacy of this method requires improvement. Baseline levels of inflammatory factors vary between individuals, but this variation tends to differ in patients with and without SSIs. Therefore, we standardized subsequently acquired concentrations of interleukin 6 and C-reactive protein in fluids drained from surgical sites by dividing them by the concentrations determined at day 1 to preclude the confounding effects of differences in baseline levels. The standardized concentrations had higher predictive efficacy than the absolute concentrations. Standardizing the data rendered SSI prediction more precise and practical in a diverse group of real patients. This translational study suggests that inflammatory factors in fluid drained from injury sites are promising tools for the prediction of SSI in the clinic.