Next generation sequencing is now being used to detect miRNA expression profiles in the sera of patients with different diseases. Compared to microarrays, these have shown better detection capabilities both in terms of the quality and quantity of miRNAs. These results showed that next generation sequencing is a promising method for genome-wide miRNA screening. In this study, we first used Solexa sequencing to screen for serum miRNAs among 9 surviving and 9 non-surviving sepsis patients. Then, qRT-PCR was used to validate the Solexa sequencing results in a cohort of 166 sepsis patients. After validation, the predictive values of the screened miRNAs were compared to those of currently used clinical biomarkers. A multivariable logistic regression analysis was also used to evaluate the predictive values and odds ratios of these miRNAs. Several circulating miRNAs have recently been reported to be biomarkers for sepsis diagnosis and prognosis. In our study, a genome-wide Solexa method was first used to screen 18 sepsis patients’ sera for miRNAs. Then, qRT-PCR was used for 196 sepsis patients to confirm the results of Solexa sequencing. Two methods for validation and a large sample size made our results more convincing. As a result, six miRNAs were confirmed to be significantly differentially expressed between sepsis survivors and non-survivors. Among these six miRNAs, the predictive value of miR-193b* for sepsis mortality was better than SOFA scores and APACHE II scores, which are both composites that integrate numerous sepsis indicators. However, serum miR-15a and miR-483-5p had poor predictive values for sepsis mortality. Thus, we used a logistic regression analysis to select those miRNAs that were associated with death from sepsis. These results showed that a combination of miR-15a, miR-16, miR-193b*, miR-483-5p, SOFA scores, APACHE II scores, and sepsis stage had a much better predictive value for mortality. Therefore, if we were to integrate these six miRNAs into a composite indicator in clinical practice, this composite indicator would have a much better predictive value for sepsis mortality than SOFA scores and APACHE II scores. These six miRNAs were differentially expressed even when survivors and non-survivors were matched by sepsis severity. Hence, these biomarkers may be genetic markers and may not necessarily be suitable for characterizing sepsis progression. Functional studies involving these biomarkers will be needed, which may provide additional valuable information for treating physicians. Previous studies of miRNAs in sepsis patients primarily focused on the miRNA expression profiles of WBCs. miR-146b, miR-150, miR-342, and miR-let-7 g were found to be differentially expressed by WBCs from healthy donors after treatment with E. Coli lipopolysaccharide infusion for 4 hours, and miR-150, miR-182, R428 miR-342-5p, and miR-486 were identified in WBCs from sepsis patients’ peripheral blood. However, none of these miRNAs were present in the expression profiles of our six miRNAs. These differences may be due to the following reasons.