Group VIB Phospholipase A(2) (iPLA(2)γ) is distributed in membranous organelles in which β-oxidation occurs, that is, mitochondria and peroxisomes, and is expressed by insulin-secreting pancreatic islet β-cells and INS-1 insulinoma cells, which can be injured by inflammatory cytokines, for example, IL-1β and IFN-γ, and by oxidants, for example, streptozotocin (STZ) or t-butyl-hydroperoxide (TBHP), via processes pertinent to mechanisms of β-cell loss in types 1 and 2 diabetes mellitus. We find that incubating INS-1 cells with IL-1β and IFN-γ, with STZ, or with TBHP causes increased expression of iPLA(2)γ mRNA and protein. We prepared INS-1 knockdown (KD) cell lines with reduced iPLA(2)γ expression, and they proliferate more slowly than control INS-1 cells and undergo increased membrane peroxidation in response to cytokines or oxidants. Accumulation of oxidized phospholipid molecular species in STZ-treated INS-1 cells was demonstrated by LC/MS/MS scanning, and the levels in iPLA(2)γ-KD cells exceeded those in control cells. iPLA(2)γ-KD INS-1 cells also exhibited higher levels of apoptosis than control cells when incubated with STZ or with IL-1β and IFN-γ. These findings suggest that iPLA(2)γ promotes β-cell proliferation and that its expression is increased during inflammation or oxidative stress as a mechanism to mitigate membrane injury that may enhance β-cell survival.