Abstract: Background - Whether and to what extent aldosterone “breakthrough” (ABT) - the undesirable phenomenon in which aldosterone exceeds pre-treatment levels despite blockade of the renin-angiotensin-aldosterone system - occurs in dogs with naturally occurring myxomatous mitral valve disease (MMVD) treated with an angiotensin receptor blocker (ARB) has not been systematically evaluated. Objectives - To compare the incidence of ABT in dogs with advanced MMVD treated with an angiotensin-converting enzyme inhibitor (ACEi; enalapril) or an ARB (telmisartan). Animals - Sixteen client-owned dogs with advanced MMVD. Methods - Prospective, randomized, masked clinical study. Serum equilibrium concentrations of aldosterone (measured using liquid chromatography-mass spectrometry) and urinary aldosterone-to-creatinine ratio (UACR; aldosterone and creatinine measured using radioimmunoassay and modified Jaffe’s method, respectively) were determined on samples collected before and after 30 days of treatment with enalapril (0.5 mg/kg PO BID) or telmisartan (1 mg/kg PO q24h). ABT was defined as any increase in serum aldosterone concentration or UACR compared to pre-treatment baseline. The proportion of dogs experiencing ABT was compared between groups using the Fisher’s exact test. Results - AABT occurred in 4 (66.7%) of 6 enalapril and 3 (33.3%) of 9 telmisartan-treated dogs based on serum aldosterone concentrations (p= 0.31), and 2 (33.3%) of 6 enalapril and 2 (22%) of 9 telmisartan-treated dogs based on UACR (p = 0.99). Conclusions and clinical importance - ABT occurs in dogs receiving an ACEi or an ARB. We did not demonstrate a difference in incidence between treatment groups, possibly due to type II error.