Abstract Purpose: The four-kallikrein (4K) panel, commercially available as the 4Kscore, has been demonstrated to improve prediction of aggressive prostate cancer (PCa) compared to prostate-specific antigen (PSA) alone or PSA in combination with free PSA. However, the development and testing of the 4K panel has been limited to studies conducted primarily in White men. Methods: We prospectively evaluated the 4K panel in a nested case-control study among African American (AA), Latino (LA), Japanese (JA), Native Hawaiian (NH), and White (WH) men in the Multiethnic Cohort (MEC). Prediagnostic blood levels of free, intact, and total PSA and human kallikrein-related peptidase 2 (hK2) were measured among 2,227 incident PCa cases and 2,189 controls. We used area under the curve (AUC) calculations to compare the discriminative ability of the 4K panel to PSA for overall PCa, Gleason-Grade Group (GGG) 2 or higher, aggressive PCa (Gleason>7, non-localized disease, or death from PCa), and death due to PCa within and across all racial/ethnic groups. Results: The mean ages of the cases and controls at blood draw were 68 (range 47–86) and 69 (range 47–87), respectively, and for cases, samples were drawn an average of 4.9 years prior to their PCa diagnosis (range <1–18 years). For men with elevated PSA (≥2.0 ng/ml; 1,669 cases and 663 controls), the AUC for overall PCa was 0.76 (95% CI 0.74–0.78) for the 4K panel compared to 0.72 (95% CI 0.70–0.74) for free plus total PSA and 0.67 (95% CI 0.65–0.70) for total PSA alone. Discrimination was slightly enhanced for the 4K panel for GGG≥2 (1,067 cases; 0.78 for panel versus 0.74 for free plus total PSA and 0.68 for total PSA only) and aggressive PCa (542 cases; 0.79 for panel versus 0.74 for free plus total PSA and 0.68 for total PSA only). Improvement of the 4K panel over total PSA alone was observed in each racial/ethnic group for all four PCa outcomes, most notably for GGG≥2 (AA, 0.71 vs. 0.66; LA, 0.82 vs. 0.71; JA, 0.80 vs. 0.69; NH, 0.90 vs. 0.77; WH, 0.77 vs. 0.69) and aggressive PCa (AA, 0.72 vs. 0.67; LA, 0.81 vs. 0.70; JA, 0.81 vs. 0.69; NH, 0.91 vs. 0.73; WH, 0.77 vs. 0.67). Conclusion: The superior predictive ability of the 4K panel over PSA for overall and aggressive PCa across multiethnic populations indicates the broad clinical applicability of the 4K panel. This abstract is also being presented as Poster A068. Citation Format: Burcu F. Darst, Peggy Wan, Alisha Chou, Emily Vertosick, David V. Conti, Lynne Wilkens, Loic Le Marchand, Andrew Vickers, Hans Lilja, Christopher A. Haiman. The four-kallikrein panel discriminates prostate cancer and aggressive disease in a multiethnic population abstract. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR01.