The acute phase protein group IIA secretory phospholipase A(2) (sPLA(2)-IIA) has intrinsic proatherosclerotic properties. The present prospective cohort study investigated whether plasma sPLA(2)-IIA associates with graft failure, cardiovascular, and all-cause mortality in renal transplant recipients (RTRs), patients with accelerated atherosclerosis formation both systemically and within the graft. In 511 RTRs from a single academic center with stable graft function >1 year, baseline plasma sPLA(2)-IIA was determined by ELISA. Primary end points were death-censored graft failure and mortality (median follow-up, 7.0 years). Baseline sPLA(2)-IIA was higher in RTRs than in healthy controls (median 384 ng/dL (range 86-6951) vs. 185 ng/dL (range 104-271), p <0.001). Kaplan-Meier analysis demonstrated increased risk for graft failure (p = 0.002), as well as cardiovascular (p <0.001) and all-cause mortality (p <0.001), with increasing sPLA(2)-IIA quartiles. Cox regression showed strong associations of sPLA(2)-IIA with increased risks of graft failure (hazard ratio (HR) = 1.42 (1.11-1.83), p = 0.006), as well as cardiovascular (HR = 1.48 (1.18 1.85), p = 0.001) and all-cause mortality (HR = 1.39 (1.17 1.64), p <0.001), dependent on parameters of kidney function. Renal function during follow-up declined faster in RTRs with higher baseline sPLA(2)-IIA levels. In RTRs, sPLA(2)-IIA is a significant predictive biomarker for chronic graft failure, as well as overall and cardiovascular disease mortality dependent on kidney function. This dependency is conceivably explained by sPLA(2)-IIA impacting negatively on kidney function.