HBV-associated decompensated cirrhosis (HBV-DeCi) is attracting considerable attention due to disease acceleration and substantial mortality. Macrophages regulate the fibrotic process in DeCi. Soluble CD206 (sCD206) is primarily expressed by macrophages. We aimed to investigate whether sCD206 predicts mortality in patients with HBV-DeCi. A total of 382 patients were enrolled between February 2020 and February 2021 and divided into nonsurviving and surviving groups according to 28-day, 3-month, and 6-month outcomes. Cox regression analysis was performed to confirm the independent prognostic factors of HBV-DeCi, and Kaplan-Meier analysis was performed to draw survival curves of sCD206. The predictive value of sCD206 was assessed at three time points according to the AUROC. The serum sCD206 level was significantly higher in deceased patients than surviving patients. Multivariate analysis showed that the level of sCD206 was related to an increased risk of 28-day, 3-month, and 6-month mortality (HR = 3.914, P < 0.001; HR = 3.895, P < 0.001; and HR = 4.063, P < 0.001, respectively). Patients with higher sCD206 levels had a worse prognosis than those with lower sCD206 levels. The best separation between the decedents and survivors was obtained by using the sCD206 level (AUROC: 0.830, 0.802, and 0.784, respectively) at 28 days, 3 months, and 6 months. The macrophage-related marker serum sCD206 was associated with mortality in HBV-DeCi patients. High levels of serum sCD206 indicated a poor prognosis in these patients. Serum sCD206 has great predictive value for short-term and midterm mortality compared with the Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores.