Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be selectively pro-apoptotic in cancer cells, with minimal toxicity to normal tissues. Although this feature makes TRAIL a promising anticancer agent, not all cancer cell types are sensitive to TRAIL-induced apoptosis despite abundant expression of TRAIL receptors. Thus, combinatorial treatments to sensitize tumor cells to TRAIL-induced apoptosis have been in the focus of extensive research. Dietary lignans have shown cancer preventive and antitumorigenic activity, but the mechanisms behind these effects are poorly known. Here we observed that of the three tested lignan molecules, matairesinol (MAT) was the most effective as a death receptor-sensitizing agent. MAT sensitized the androgen-dependent LNCaP cells to TRAIL-induced apoptosis both in the presence and absence of androgens. Treatment with MAT markedly decreased Akt activity, which has been implicated as a key signaling mechanism in the TRAIL resistance of LNCaP prostate cancer cells. The involvement of the pathway in the MAT-mediated sensitization was shown in rescue experiments using ectopic expression of constitutively active Akt. Owing to the high activity of phosphatidylinositol 3-kinase/Akt signaling in cancer, targeting this survival pathway with MAT could markedly benefit TRAIL-based tumor therapies, including those aimed at prostate cancer.