End-stage renal failure is associated with persistent systemic inflammation. The aim of this study was to investigate if systemic inflammation at the time of kidney transplantation is linked to poor graft survival, major adverse cardiovascular events (MACE), and increased mortality, and if these processes are modulated by naturally occurring cytokine-specific autoantibodies (c-aAbs), which have been shown to regulate cytokine activity in vitro. Serum levels of cytokines, high-sensitivity C-reactive protein (hsCRP) and c-aAbs specific for interleukin (IL)-1α, tumor necrosis factor (TNF)-α, IL-6, and IL-10 were measured at the time of transplantation in a retrospective cohort study of 619 kidney transplanted patients with a median follow-up of 4.9 years (range 1.2 to 8.2 years). Systemic inflammation was associated with all-cause mortality in simple and multiple Cox regression analyses. IL-10-specific c-aAbs were associated with MACE after transplantation, suggesting that IL-10 may be a protective factor. Similarly, patients with a history of MACE before transplantation had lower levels of TNF-α-specific c-aAbs, hence we hypothesized that TNF may be a risk factor of MACE. These findings support that pro-inflammatory activity before transplantation is a pathological driver of MACE and all-cause mortality after transplantation. This information adds to pre-transplantation risk estimation in renal transplant candidates. This article is protected by copyright. All rights reserved.