For some patient subgroups, HIV-infection has been associated with worse outcomes after kidney transplantation (KT); potentially modifiable factors may be responsible. The study goal was to identify factors that predict a higher risk of graft loss among HIV+ KT recipients compared with a similar transplant among HIV− recipients. 82,762 deceased donor KT (HIV+: 526; HIV−: 82,236) reported to SRTR (2001–2013) were studied by interaction term analysis. Compared to HIV− recipients, HCV amplified risk 2.72-fold among HIV+ KT recipients (aHR: 2.72, 95%CI: 1.75–4.22, p<0.001); and 43% of the excess risk was attributable to the interaction between HIV and HCV (AP: 0.43, 95%CI: 0.23–0.63, p=0.02). Among HIV+ recipients with >3 HLA mismatches (MM), risk was amplified 1.80-fold compared to HIV− (aHR: 1.80, 95% CI: 1.31–2.47, p < 0.001); and 42% of the excess risk was attributable to the interaction between HIV and >3 HLA MM (AP: 0.42, 95%CI: 0.24–0.60, p=0.01). High-HIV-risk (HIV+/HCV+ & >3 HLA MM) recipients had a 3.86-fold increased risk compared to low-HIV-risk (HIV+/HCV− & ≤3 HLA MM) recipients (aHR: 3.86, 95%CI: 2.37–6.30, p< 0.001). Avoidance of >3 HLA mismatches in HIV+ KT recipients, particularly among co-infected patients, may mitigate the increased risk of graft loss associated with HIV-infection.