Background: Acute stress induced (takotsubo) cardiomyopathy can result in a heart failure phenotype with a prognosis comparable to myocardial infarction. In this study, we hypothesized that inflammation is central to the pathophysiology and natural history of takotsubo cardiomyopathy. Methods: In a multi-centre study, we prospectively recruited 55 patients with takotsubo cardiomyopathy and 51 age, sex and co-morbidity matched control subjects. During the index event and at 5 months follow-up, patients with takotsubo cardiomyopathy underwent multiparametric cardiac magnetic resonance imaging including ultrasmall superparamagnetic particles of iron oxide (USPIO) enhancement for detection of inflammatory macrophages in the myocardium. Blood monocyte subpopulations and serum cytokines were assessed as measures of systemic inflammation. Matched controls underwent investigation at a single time point. Results: Subjects were predominantly middle aged (64±14years) women (90%). When compared to control subjects, patients with takotsubo cardiomyopathy had greater USPIO enhancement (expressed as the difference between pre-USPIO and post-USPIO T2*) in both ballooning (14.3±0.6 versus 10.5±0.9 ms, p<0.001) and non-ballooning (12.9±0.6 versus 10.5±0.9 ms, p=0.02) left ventricular myocardial segments. Serum interleukin-6 (23.1±4.5 versus 6.5±5.8 pg/mL, p< 0.001) and chemokine (C-X-C motif) ligand 1 (1903±168 versus 1272±177 pg/mL, p=0.01) concentrations, and classical CD14++CD16- monocytes (90±0.5 versus 87±0.9%, p=0.01) were also increased whilst intermediate CD14++CD16+ (5.4±0.3 versus 6.9±0.6%, p=0.01) and non-classical CD14+CD16++ (2.7±0.3% versus 4.2±0.5%, p=0.006) monocytes were reduced in patients with takotsubo cardiomyopathy. At 5 months, USPIO enhancement was no longer detectable in the left ventricular myocardium although there remained persistent elevations in serum interleukin-6 concentrations (p=0.009) and reductions in intermediate CD14++CD16+ monocytes (5.6±0.4 versus 6.9±0.6%, p=0.01). Conclusions: We demonstrate for the first time that takotsubo cardiomyopathy is characterized by a myocardial macrophage inflammatory infiltrate, changes in the distribution of monocyte subsets and an increase in systemic pro-inflammatory cytokines. Many of these changes persisted for at least 5 months suggesting a low-grade chronic inflammatory state. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique identifier: NCT02897739 Key Words: