Receptivity to recommended colorectal cancer (CRC) screening can be enhanced by the use of loss-framed health messaging that emphasizes the possible consequences of failing to act. However, a simultaneous use of culturally targeted messaging may be needed to achieve effectiveness when loss-framed messaging is used with African Americans, especially to reduce racism-related cognitions aroused by standard loss-framing that impede CRC screening receptivity. This study considered whether the effects of stand-alone and culturally targeted message framing on CRC screening receptivity differ between African American men and women. African Americans eligible for CRC screening (men = 117, women = 340) viewed an informational video about CRC risks, prevention, and screening and were randomized to receive a gain- or loss-framed message about screening. Half of the participants received an additional culturally targeted message. Using the theory of planned behavior, we measured receptivity to CRC screening. We also measured the arousal of racism-related cognitions. A significant three-way interaction suggested effects of messaging on CRC screening receptivity were moderated by gender. Participants were no more receptive to CRC screening when standard loss-framing was used but were more favorable if loss-framing was culturally targeted. However, these effects were more pronounced among African American men. Contrary to prior findings, gender moderated the effects of culturally targeted loss-framed messaging were not attributable to reducing racism-related cognitions. Findings add to the growing recognition of important nuance in the effective use of message framing to also include gender, while suggesting a critical need to explore gender-relevant mechanistic pathways, potentially including how health messaging activates masculinity-related cognitions among African American men.