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The purpose of this study was to characterize associations among serum proteins, negative-pressure wound therapy (NPWT) fluid loss, and primary fascial closure (PFC) following emergent laparotomy and temporary abdominal closure (TAC). We hypothesized that high levels of C-reactive protein (CRP) and NPWT output would be associated with hypoalbuminemia and failure to achieve PFC.We performed a retrospective analysis of 233 patients managed with NPWT TAC. Serum proteins and resuscitation indices were assessed on admission, initial laparotomy, and then at 48 hours, 96 hours, 7 days, and discharge. Correlations were assessed by Pearson coefficient. Multivariable regression was performed to identify predictors of PFC with cutoff values for continuous variables determined by Youden index.Patients who failed to achieve PFC (n = 55) had significantly higher CRP at admission (249 vs. 148 mg/L, p = 0.003), initial laparotomy (237 vs. 154, p = 0.002), and discharge (124 vs. 72, p = 0.003), as well as significantly lower serum albumin at 7 days (2.3 vs. 2.5 g/dL, p = 0.028) and discharge (2.5 vs. 2.8, p = 0.004). Prealbumin (in milligrams per deciliter) was similar between groups at each time point. There was an inverse correlation between nadir serum albumin and total milliliters of NPWT output (r = −0.33, p < 0.001). Exogenous albumin administration (in grams per day) correlated with higher serum albumin levels at each time point: 48 hours: r = 0.26 (p = 0.002), 96 hours: r = 0.29 (p = 0.002), 7 days: r = 0.40 (p < 0.001). Albumin of less than 2.6 g/dL was an independent predictor of failure to achieve PFC (odds ratio, 2.59; 95% confidence interval, 1.02–6.61) in a multivariate model including abdominal sepsis, body mass index of greater than 40 kg/m2, and CRP of greater than 250 mg/L.Early and persistent systemic inflammation and high NPWT output were associated with hypoalbuminemia, which was an independent predictor of failure to achieve PFC. The utility of exogenous albumin following TAC requires further study.Prognostic study, level III; Therapeutic study, level IV.