Few empirical studies have focused on the associations among suicide proneness, hopelessness, and depression cross-culturally. The current study examined the potential to determine differences in the overall expression of suicide proneness between Japanese (n = 396) as compared with U.S. (n = 417) college students. Depressive symptoms were considered as a potential mediator of the relation between hopelessness and suicide proneness in both samples of students. Preliminary analyses focused on estimates of internal consistency reliability and differential item functioning (DIF) on the measures of hopelessness, depressive symptoms, and suicide proneness. Results of the primary analyses revealed that Japanese students reported more suicide proneness, greater hopelessness, and higher levels of depressive symptoms than did U.S. students. As expected, hopelessness and depressive symptoms were significantly associated with suicide proneness in both cultures. Additionally, the hopelessness–suicide proneness link was significantly mediated by depressive symptoms in both samples. Implications are offered for improved identification and treatment of college students at risk of suicidal behaviors both in the United States and in Japan.