Background We investigate if renin‐angiotensin and endothelin‐1 response pathways follow the same pattern of recovery as left ventricular ejection fraction in patients with takotsubo cardiomyopathy. Methods and Results Ninety patients with takotsubo cardiomyopathy (n=30 in each of “acute,” “convalescent” [3–5 months] and “recovered” [>1 year] groups) who were on minimal or no medication and were free of any significant cardiac/metabolic comorbidities, and 30 controls were studied. Serum concentrations of renin, angiotensin‐converting enzyme, angiotensin II, big endothelin‐1, endothelin‐1 were measured using commercially available ELISA, and B‐type natriuretic peptide was measured using an immunoassay. Mean left ventricular ejection fraction was <40% during the acute phase in all groups, but recovered to 63% in convalescent and 64% in the recovered groups, respectively. Serum renin concentrations remain persistently elevated after a episode of takotsubo cardiomyopathy ( P =0.03 versus controls). Angiotensin converting enzyme levels are significantly depressed during the acute phase compared with convalescent ( P =0.004), recovered takotsubo cardiomyopathy ( P =0.02) or controls ( P =0.03). Angiotensin II is increased in patients with takotsubo cardiomyopathy ( P <0.001 versus controls) remaining persistently elevated in the chronically recovered group alone ( P =0.03 versus controls). Big endothelin‐1 levels are unchanged, but endothelin‐1 is significantly lower after takotsubo cardiomyopathy compared with controls ( P =0.03). Conclusions Despite “normalization” of the left ventricular ejection fraction, there is long‐term maladaptive activation of renin‐angiotensin system in patients with takotsubo cardiomyopathy. Registration URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02897739, NCT02989454.