We analyzed whether there is an interaction between the Kidney Donor Index (KDPI) and cold ischemia time (CIT) in recipients of deceased donor kidney transplant (KT). Adults who underwent KTs in the United States between 2014 and 2020 were included and divided into three KDPI groups ( 85%) and four CIT strata (< 12, 12-17.9, 18-23.9, ≥ 24 hours). Multivariate analyses were used to test the interaction between KDPI and CIT for the following outcomes: primary graft non-function (PGNF), delayed graft function (DGF), estimated glomerular filtration rate at 6 and 12 months, patient survival, graft survival, and death-censored graft survival. A total of 69,490 recipients were analyzed: 18,241 (26.3%) received a graft with KDPI 85%. We confirmed that increasing KDPI and CIT were associated with worse post-KT outcomes. Contrary to our hypothesis, the interaction between KDPI and CIT was statistically significant only for PGNF and DGF. In addition, the negative coefficient of the interaction suggested that increasing duration of CIT was more detrimental for low and intermediate KDPI organs relatively to high KPDI grafts. Conversely, for mortality, graft survival, and death-censored graft survival, we found that the interaction between CIT and KDPI was not statistically significant. We conclude that although, high KDPI and prolonged CIT are independent risk factors for inferior outcomes after KT, their interaction is significant only for the short-term outcomes after KT with more pronounced effects on low and intermediate KDPI grafts. SIGNIFICANCE STATEMENT: Kidney Donor Profile Index (KDPI) and Cold Ischemia Time (CIT) are both independent predictors of post-transplant outcomes. However, there is very limited literature on the interaction between these two factors. In this study, we analyzed United States national data and confirmed that lower KDPI values and shorter CIT are associated with the best short- and long-term posttransplant outcomes. However, even for recipients of high-KDPI kidneys (>85%) with long CIT (> 24 hours), posttransplant outcomes were acceptable and, contrary to our hypothesis, we found no evidence that there is a significant interaction between KDPI and CIT on patient or graft survival. We therefore conclude that, although CIT should be always minimized, adequate post-transplant outcomes are possible even with selected high-KDPI kidneys with prolonged CIT.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.