Fucoidan, a fucose-rich polysaccharide extracted from brown seaweed, has antitumor, anticoagulant, antiviral, anti-inflammatory, and antibacterial activities. Several studies have shown that a fucoidan treatment of cancer cells induced cytotoxicity and apoptosis and inhibited angiogenesis and invasion. We investigated in the present study the effect of low-molecular-weight fucoidan (LMWF) on apoptosis in estrogen receptor-negative MDA-MB-231 human breast cancer cells. The LMWF treatment of MDA-MB-231 cells was associated with the activation of caspases and mitochondrial dysfunction, including dissipation of the mitochondrial membrane potential (ΔΨm), alteration of Ca(2+) homeostasis, cytochrome c release, and decreased expression of antiapoptotic Bcl-2 family proteins. Understanding the molecular events that mediated LMWF-induced MDA-MB-231 cell death will contribute to a more rational approach to cancer chemotherapy.