Objective: NOD-like receptor protein 1 (NLRP1) inflammasome complex has been recently associated with chronic unpredictablemild stress (CUMS) model of depression. Our aim was to investigate whether ketamine-induced antidepressant effect is associated withsuppression of NLRP1. Methods: Wistar albino rats were divided into control, CUMS, CUMS+acute ketamine (a single 10 mg/kg dose) and CUMS+chronicketamine (daily 10 mg/kg injections for 3 weeks) groups (n=10 for each group). Sucrose preference test and forced swimming test wereperformed to assess anhedonia and immobility time respectively for the severety of depression symptoms. Brain tissues were dissectedand prefrontal cortex and hippocampus regions were used for real-time polymerase chain reaction (PCR) and immunohistochemicalanalysis. Results: CUMS procedure significantly induced depressive-like symptoms whereas both acute and chronic ketamine treatment amelioratedthem. mRNA expression levels of NLRP1, caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), NF-κB,endothelial nitric oxide synthase, IL-1β, IL-6, toll-like receptor 4 (TLR-4) and purinergic 2×7 receptor (P2X7R) and numbers of Iba-1+and GFAP+glial cells were reduced by acute and/or chronic ketamine treatment. Conclusion In the present study for the first time upstream and downstream elements of the NLRP1 inflammasome complex are shownto be suppressed by ketamine thus reinforcing the involvement of NLRP1 in the physiopathology of depression.Psychiatry Investig 2020;17(4):283-291