Abstract Background The pathophysiologic mechanisms and the prognostic meaning of electrocardiographic (ECG) T-wave inversion (TWI) occurring in a subgroup of patients with clinically suspected acute myocarditis remain to be elucidated. Contrast-enhanced cardiac magnetic resonance (CMR) offers the potential to identify myocardial tissue changes such as edema and/or fibrosis which may underlie TWI. Methods and results We studied 76 consecutive patients (median age 34 years) with clinically suspected acute myocarditis, using a comprehensive CMR protocol which included T2 weighted sequences for myocardial edema. At the time of CMR, TWI was observed in 21 (27%) patients. There was a statistically significant association of TWI with the median number of left ventricular (LV) segments showing both any pattern of myocardial edema (transmural and non-transmural) 5 (3-7) vs. 3 (2-4); p = 0.015 and myocardial late-gadolinium-enhancement 4 (3-7) vs. 3 (2-4); p = 0.002. Transmural myocardial edema involving ≥ 2 LV segments was found in 17/21 (81%) patients with TWI versus 13/55 (24%) patients without TWI ( p < 0.001) and remained the only independent predictor of TWI at multivariable analysis (OR = 9.96; 95%CI = 2.71–36.6; p = 0.001). Overall, topographic concordance between the location of TWI across the ECG leads and the regional distribution of transmural myocardial edema was 88%. There was no association between acute TWI and reduced LV ejection fraction (< 55%) at 6-months of follow-up. Conclusions This is the first study to demonstrate an association between LV transmural myocardial edema as evidenced by CMR sequences and TWI in clinically suspected acute myocarditis. As an expression of reversible myocardial edema, development of TWI during the acute disease phase was not a predictor of LV systolic dysfunction at follow-up.