SGN-30, a chimeric monoclonal antibody with apoptotic-signaling activity against CD30-positive malignancies, is currently in Phase II clinical evaluation against anaplastic large cell lymphoma and Hodgkin’s disease (HD). Mechanisms underlying SGN-30’s anti-tumor activity were evaluated using cDNA array analysis of SGN-30-treated L540 HD cells. Changes in expression of growth and apoptotic related genes including cyclin D2 and p21CIP1/WAF1 followed treatment of L540 and L540cy cells with SGN-30. Intra-cellular staining showed increases in both activated caspase-3 and p21CIP1/WAF1 in L540cy. These alterations coincided with increased Annexin V/PI staining. In addition to directly inducing apoptosis, SGN-30 mediated alterations in gene expression and could sensitize cells to standard chemotherapeutics. To evaluate this potential, L540cy cells were treated for 24 h with SGN-30 followed by exposure to a panel of chemotherapeutics commonly used in HD therapy and the combinations quantified by the Combination Effects method. Most of the chemotherapies examined were at least additive or better in combination with SGN-30, with bleomycin producing the strongest synergistic response. In vitro data were confirmed by the significantly increased efficacy of SGN-30 and bleomycin against established L540cy HD tumor xenografts in SCID mice. Results suggest that in addition to direct cell killing, SGN-30 binding to CD30 on HD tumor cells effects both growth arrest and drug sensitization by altering gene expression of cell cycle and apoptotic-related genes. Importantly, tumor cell sensitization to established chemotherapies, in particular DNA damaging agents used to treat HD, suggests that SGN-30 could improve the outcome of current drug-based therapies for treating HD.