A decreased glomerular filtration rate (GFR) is a risk factor for cardiovascular disease even after adjustment for conventional risk factors. The myocardial performance index (MPI) is defined as (isovolumetric relaxation time (IVRT) + isovolumetric contraction time (IVCT))/ejection time (ET). It has been shown to be an independent predictor of cardiovascular events. We hypothesized the MPI could prove valuable for assessing cardiac risk in subjects of the general population with decreased estimated GFR (eGFR). MPI was measured in 1915 subjects from a large general population prospective cohort study using color tissue Doppler imaging (TDI) M-mode through the mitral valve. We compared the prognostic capabilities of the MPI between subjects with eGFR ≥ 75 mL/min/1.73 m² and subjects with eGFR < 75 mL/min/1.73 m² using multivariable adjusted Cox regression models. The composite endpoint was heart failure, myocardial infarction or cardiovascular death. Mean age was 58 years (SD 16.2), 58% were women, 42% had hypertension and 8.3% diabetes. During a median follow-up time of 12.4 years [IQR 10.6–12.7 years] 269 participants reached the combined endpoint. eGFR modified the prognostic capability of MPI (p-value for interaction < 0.001): After multivariable adjustment, MPI remained an independent predictor of the composite endpoint only in participants with eGFR < 75 mL/min/1.73 m²: HR 1.18 (95% CI 1.02–1.38), p = 0.03, vs. in subjects with eGFR ≥ 75 mL/min/1.73 m²: HR 1.14 (95% CI 0.94–1.39), p = 0.17. These results suggest the MPI could be particularly valuable for identifying elevated cardiac risk in individuals from the general population with decreased eGFR.