Crystalline monosodium urate (MSU) produces inflammation in vivo and kills phagocytes in vitro. A plausible hypothesis to account for crystal-induced cell death is that ingested crystals perforate the phagocytic vacuole into which lysosomes have degranulated: “lysis from within.” However, it has also been contended that degranulation is not required for crystal-induced cell death. To resolve this controversy, we have prepared neutrophil-derived cytoplasts (“neutroplasts”) which are devoid of most cellular organelles, including lysosomal granules. Both intact neutrophils and neutroplasts ingested MSU crystals, but inhibition of phagocytosis by cytochalasin B reduced crystal-induced death of neutrophils (release of lactate dehydrogenase) from 42% to 16% without altering lysis of neutroplasts (27% with MSU alone and 26% with MSU and cytochalasin B). Moreover, addition of serum, which prevents direct interaction of crystals with the outer plasma membrane, reduced lysis of neutrophils, reducing cell death from 42% to 25%. After 60 min incubation, serum was totally ineffective in reducing neutrophil death but continued to reduce lysis of neutroplasts from 61% to 13%. Thus, the MSU lysed neutroplasts under conditions in which it ruptured membranes of nonphagocytic structures (erythrocytes, liposomes), i.e., in the absence of serum: “lysis from without.” These data suggested that death of neutrophils after internalization of MSU requires a component that is lacking in neutroplasts. Granules (lysosomes) are the best candidates for this component, supporting the general validity of the “lysis from within” hypothesis.