Black women who use substances in the United States face unique human immunodeficiency virus (HIV) risk factors. However, interventions addressing cultural factors relevant for preventing HIV risk behaviors among Black women are limited. This project aimed to develop and initially test the effectiveness of a culturally adapted version of safer sex skills building (SSSB), an evidence-based HIV prevention intervention for reducing HIV risk among Black women who use substances. The cultural adaptation procedures involved (i) review of existing literature, (ii) use of Delphi process and theater testing to generate an adapted version, (iii) theater testing of the culturally adapted version and (iv) initial testing. Forty-eight Black women recruited from a substance use treatment clinic in the United States participated in three 2.5-h sessions of a culturally adapted or a generic version of the intervention. More (48%) women in the culturally adapted version self-reported condom use with casual partners compared to women in the generic (29%) version at a 6-week follow-up. The two groups did not differ on self-reported condom use with main partners. The culturally adapted SSSB offers a promising intervention for sexual risk reduction among Black women who use substances. Moreover, the findings advance the field by illustrating a concrete methodology for cultural adaptation.