Background Development and progression of myxomatous mitral valve disease (MMVD) in dogs are difficult to predict. Identification at a young age of dogs at high risk of adverse outcome in the future is desirable. Hypothesis/Objectives To study the predictive value of selected clinical and echocardiographic characteristics associated with MMVD obtained at a young age for prediction of long-term cardiac and all-cause mortality in Cavalier King Charles Spaniels (CKCS). Animals 1125 privately owned CKCS. Methods A retrospective study including CKCS examined at the age of 1–3 years. Long-term outcome was assessed by telephone interview with owners. The value of variables for predicting mortality was investigated by Cox proportional hazard and Kaplan-Meier analyses. Results Presence of moderate to severe mitral regurgitation (MR) (hazard ratio (HR) = 3.03, 95% confidence interval (95% CI) = 1.48–6.23, P = 0.0025) even intermittent moderate to severe MR (HR = 2.23, 95% CI = 1.48–6.23, P = 0.039) on color flow Doppler echocardiography was significantly associated with increased hazard of cardiac death. An interaction between MR and sex was significant for all-cause mortality (P = 0.035), showing that males with moderate to severe MR had a higher all-cause mortality compared to males with no MR (HR = 2.38, 95% CI = 1.27–4.49, P = 0.0071), whereas no difference was found between female MR groups. The risk of cardiac (HR = 1.37, 95% CI = 1.14–1.63, P < 0.001) and all-cause (HR = 1.13, 95% CI = 1.02–1.24, P = 0.016) mortality increased with increasing left ventricular end-systolic internal dimension normalized for body weight (LVIDSN). Conclusions and clinical importance Moderate to severe MR, even if intermittent, and increased LVIDSN in dogs <3 years of age were associated with cardiac death later in life in CKCS.