This study seeks to examine the influence of key cultural values like machismo, familism, traditionalism, and religiosity on self-efficacy in reducing HIV risk among Mexican-origin IDUs. The purpose of this examination hinges on the importance of including cultural concepts/values not only to facilitate process, but also to add a cultural dimension to an HIV/AIDS intervention that may facilitate attitudinal and behavioral change as well. The findings suggest that culturally innovative approaches can facilitate HIV/AIDS risk reduction among male Mexican-origin drug injectors. The importance of key cultural values like machismo is underscored by its association with HIV risk reduction for both sexual and injection related risks. Intervention programs must identify strategies to incorporate cultural values in their research and evaluation of intervention efficacy. Culturally innovative approaches hold the promise of substantially reducing HIV risk behaviors among Hispanic drug injectors, and may hold promise for other populations affected by HIV/AIDS as well.