BACKGROUND Fucoxanthin is a carotenoid present in the chloroplasts of brown seaweeds. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively induces apoptosis in many tumor cells and is an attractive candidate for antitumor therapies. MATERIAL AND METHODS After human cervical cancer cell lines HeLa, SiHa, and CaSki were treated with fucoxanthin or TRAIL. Cell viability was determined by 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2-tetrazolium 5-carboxanilide (XTT) method. Apoptosis was measured by flow cytometry (FCM). Protein expression of phosphatidylinositol 3 kinase (PI3K), protein kinase B (Akt), phosphated Akt (p-Akt), NF-κB nuclear factor-k-gene binding (NF-κB). Phosphated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (p-IκBα), was measured by Western blot analysis. mRNA expression of Bax and Bcl2 was measured by RNA preparation and quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS In the present study, the effectiveness in terms of apoptosis was as follows: TRAIL plus fucoxanthin>fucoxanthin>TRAIL, indicating the combination of fucoxanthin and TRAIL, produced a strong synergistic effect on apoptosis in human cervical cancer cells. Additionally, we found that upstream signaling PI3K/Akt and NF-κB pathways-mediated cell apoptosis was activated by TRAIL and suppressed by fucoxanthin. By using PI3K and NF-κB inhibitors LY49002 and PDTC, we found that fucoxanthin- or TRAIL-induced apoptosis of human cervical cancer cells was obviously down-regulated. CONCLUSIONS Taken together, these findings suggest that fucoxanthin and TRAIL increased the apoptosis in human cervical cancer cells by targeting the PI3K/Akt/NF-κB signaling pathway.