Purpose Active immunization against the tumor-specific MAGE-A3 antigen is followed by a few but impressive and durable clinical responses. This randomized phase II trial evaluated two different immunostimulants combined with the MAGE-A3 protein to investigate whether a more robust and persistent immune response could be associated with increased clinical benefit. Patients and Methods Patients with MAGE-A3–positive stage III or IV M1a melanoma were randomly assigned to receive the MAGE-A3 protein combined either with AS02_B or with AS15 immunostimulant. Clinical end points were toxicity and rates of objective clinical responses, progression-free survival (PFS), and overall survival (OS). Results Seventy-five patients were treated, with 36 eligible patients per arm. Both treatments were well tolerated. In the AS15 arm, four objective responses were observed (three complete responses and one partial response) versus one partial response in the AS02_B arm. In the AS15 and AS02_B arms, the PFS rates after 6 months were 25% and 14%, respectively; and the median OS times were 33 months and 19.9 months, respectively, with a median observation period of 48 months. Antibodies against MAGE-A3, found in all patients, showed three-fold higher titers in the AS15 arm. The anti–MAGE-A3 cellular response was also more pronounced in the AS15 arm. Conclusion In the MAGE-A3+AS15 arm, clinical activity was higher and the immune response more robust. Therefore, the AS15 immunostimulant was selected for combination with the MAGE-A3 protein in phase III trials.