Objective To investigate the expression levels of interleukin-18 (IL-18), interleukin-1β (IL-1β), nod-like receptor protein 3 (NLRP3), cysteinyl aspartate specific proteinase (Caspase)-1 in the supernatant of peripheral blood mononuclear cells (PBMC) of patients with severe chronic hepatitis B (CHB), and analyze their relationship with the prognosis of patients. Method A total of 251 CHB patients admitted in Hainan West Central Hospital from January 2019 to January 2021 were gathered as the research group. According to the severity of patients, they were divided into mild CHB group (93 cases), moderate CHB group (80 cases), and severe CHB group (78 cases). According to whether severe CHB patients died after 6 months of treatment, the patients were divided into a death group (11 cases) and a survival group (67 cases). In addition, 265 healthy people who came to our hospital for physical examination during the same period were selected as the control group. Enzyme-linked immunosorbent assay (ELISA method) was used to detect the expression levels of IL-18, IL-1β, NLRP3 and Caspase-1 in the supernatant of PBMC culture; Kaplan-Meier method was used to analyze the relationship between the levels of IL-18, IL-1β, NLRP3, Caspase-1 and the prognosis of patients with severe CHB; multivariate Logistic regression was used to analyze the factors influencing the prognosis of patients with severe CHB. Result The levels of IL-18, IL-1β, NLRP3 and Caspase-1 [(65.86±21.32) pg/ml, (68.06±22.44) pg/ml, (241.57±104.07) pg/ml, (179.01±81.46) pg/ml] in the PBMC culture supernatant of the study group were higher than those in the control group [(32.11±8.95) pg/ml, (25.49±7.06) pg/ml, (87.61±23.70) pg/ml, (10.33±3.29) pg/ml], with statistically significant differences (all P<0.05); the levels of IL-18, IL-1β, NLRP3 and Caspase-1 in the PBMC culture supernatant of patients in mild CHB group, moderate CHB group and severe CHB group increased in turn [IL-18: (50.66±12.80) pg/ml, (70.29±19.03) pg/ml, (79.43±20.56) pg/ml, IL-1β: (51.23±13.17) pg/ml, (72.91±18.64) pg/ml, (83.15±21.78) pg/ml, NLRP3: (136.13±34.95) pg/ml, (289.61±73.08) pg/ml, (318.01±80.50) pg/ml, Caspase-1: (100.26±27.03) pg/ml, (201.30±54.15) pg/ml, (250.04±67.42) pg/ml], with statistically significant differences (all P<0.05); the levels of IL-18, IL-1β, NLRP3 and Caspase-1 [(104.40±10.36) pg/ml, (110.32±11.57) pg/ml, (367.03±32.25) pg/ml, (292.34±36.28) pg/ml] in the PBMC culture supernatant of the death group were significantly higher than those of the survival group [(75.33±19.82) pg/ml, (78.69±21.39) pg/ml, (309.96±71.19) pg/ml, (241.10±61.44) pg/ml], with statistically significant differences (all P<0.05); Kaplan-Meier results showed that the survival rate (75.6%, 73.7%, 75.6%, 76.9%) of patients with severe CHB in the high expression group of IL-18, IL-1β, NLRP3, and Caspase-1 were lower than that in the low expression group (97.3%, 97.5%, 97.3%, 94.9%) (all P<0.05); model for end-stage liver disease (MELD) score, international normalized ratio (INR) and IL-18, IL-1β, NLRP3, Caspase-1 levels were independent risk factors affecting the prognosis of patients with severe CHB (OR=1.821, 1.693, 2.866, 3.514, 2.007, 2.354, all P<0.05). Conclusion The elevated levels of IL-18, IL-1β, NLRP3, and Caspase-1 in the PBMC culture supernatant of patients with severe CHB are related to the poor prognosis of patients, and can be used as auxiliary indicators for prognostic evaluation of patients with severe CHB.