OBJECTIVE Type 2 diabetes is characterized by increased death rate. In order to tackle this dramatic event, it becomes essential to discover novel biomarkers capable of identifying high-risk patients to be exposed to more aggressive preventive and treatment strategies. hs-CRP and serum amyloid P component (SAP) are two acute-phase inflammation proteins, which interact physically and share structural and functional features. We investigated their combined role in associating with and improving prediction of mortality in type 2 diabetes. RESEARCH DESIGN AND METHODS Four cohorts comprising 2,499 patients with diabetes (643 all-cause deaths) were analyzed. The improvement of mortality prediction was addressed using two well-established prediction models, namely, EstimatioN oF mORtality risk in type 2 diabetiC patiEnts (ENFORCE) and Risk Equations for Complications of Type 2 Diabetes (RECODe). RESULTS Both hs-CRP and SAP were independently associated with all-cause mortality (hazard ratios [HRs] [95% CIs]: 1.46 [1.34–1.58] [P < 0.001] and 0.82 [0.76–0.89] [P < 0.001], respectively). Patients with SAP ≤33 mg/L were at increased risk of death versus those with SAP >33 mg/L only if hs-CRP was relatively high (>2 mg/L) (HR 1.96 [95% CI 1.52–2.54] [P < 0.001] and 1.20 [0.91–1.57] [P = 0.20] in hs-CRP >2 and ≤2 mg/L subgroups, respectively; hs-CRP-by-SAP strata interaction P < 0.001). The addition of hs-CRP and SAP significantly (all P < 0.05) improved several discrimination and reclassification measures of both ENFORCE and RECODe all-cause mortality prediction models. CONCLUSIONS In type 2 diabetes, hs-CRP and SAP show opposite and synergic associations with all-cause mortality. The use of both markers, possibly in combination with others yet to be unraveled, might improve the ability to predict the risk of death in the real-life setting.