Background Echocardiographic grading of secondary mitral regurgitation (SMR) severity is challenging and involves multiple guideline-recommended parameters. We previously introduced the average pixel intensity (API) method for grading SMR. In this study, the clinical outcome in SMR based on the API method for grading MR was compared with conventional grading methods. Methods 231 patients with systolic heart failure and reduced ejection fraction (ischaemic/non-ischaemic) and SMR were prospectively enrolled. MR was graded using all guideline-recommended parameters and the API method, which is based on the pixel intensity of the continuous wave Doppler signal. The primary outcome was MACE (major adverse cardiac event). Results The API method was applicable in 98% of patients with SMR (n=227). During a median follow-up of 24 months, 98 patients (43%) had a MACE (cardiovascular mortality (n=50, 22%), heart failure hospitalisation (n=44, 19%), mitral valve surgery (n=11, 5%), percutaneous mitral intervention (n=12, 5%), heart transplantation (n=5, 2%)). On log-rank test, the API method was highly significant in predicting clinical outcome. On multivariable Cox proportional hazard analysis, SMR grading with the API method was an independent predictor of clinical outcome (along with NYHA class and right ventricular systolic pressure; p<0.001), increasing the event risk by 9% per 10 au API rise (p=0.001). In the same multivariable analysis, proximal isovelocity surface area (PISA)-effective regurgitant orifice area or PISA-regurgitant volume were not independent predictors of events (p=0.18 and 0.26, respectively). Conclusion SMR grading with the API method is an independent predictor of clinical outcome and provides prognostic information in addition to clinical and other echocardiographic variables.