The depletion of peripheral blood B cells is associated with immunosuppression and poor prognosis during sepsis, and selective depletion occurs when B cell subsets are specifically targeted. In this study, we examined the mechanisms underlying the selective depletion of B cell subsets in the immunosuppressive phase of septic shock patients. Thirty-two septic shock patients were recruited as a septic shock group and 10 healthy volunteers as a control group. The expression of Bcl-2, CD95, cleaved caspase-9/8, and activated caspase-3/1 in the B cell subsets were measured by flow cytometry. Another 23 septic shock patients were recruited to test the remission of caspase-3 (Z-DEVD-FMK) and -1 (VX-765) inhibitors on B cell subset depletion in vitro. In septic shock patients, the Bcl-2 levels in immature/transitional (IM) B cells decreased and the levels of cleaved caspase-9 in IM B cells increased; The levels of CD95 in IM, naive, resting memory (RM), and activated memory (AM) B cells and the levels of cleaved caspase-8 in IM, RM, and AM B cells increased; The levels of activated caspase-3 and caspase-1 in IM, RM, and AM B cells increased. Activated caspase-1 levels in IM B cells were higher compared with activated caspase-3 in septic shock patients, whereas the levels of activated caspase-1 in AM B cells were lower compared with activated caspase-3. Moreover, in vitro experiments showed that Z-DEVD-FMK and VX-765 could alleviate the depletion of IM, AM, and RM B cells. The selective reduction of circulating B cell subsets in septic shock patients could be attributed to intrinsic and extrinsic apoptosis as well as pyroptosis.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.