Introduction: Cardiovascular (CV) involvement in multisystem inflammatory syndrome in children (MISC) is frequent (80-85%). Data on 2D speckle tracking echocardiography and its value in predicting CV outcomes are limited. Hypothesis: We hypothesized that an association exists between 2D speckle tracking strain/strain rate parameters at admission and adverse CV outcomes during hospitalization (inotropic support, major arrhythmias, cardiac arrest, ECMO, death, or transplant). Methods: We performed a multicenter (33 centers) cohort study on MISC patients hospitalized from 03/2020 to 11/2021 with at least one echocardiogram read by the Core Lab. The association between each 2D speckle tracking strain parameter and adverse CV outcomes was assessed by logistic regression. Results: Of 349 patients (median age 8.7 years [IQR 5.3,12.9]), 122 (35%) had decreased left ventricle (LV) ejection fraction (EF) and 156 (45%) had depressed LV 4-chamber longitudinal strain (LS) or basal circumferential strain (CS) during hospitalization. Worst EF and strain occurred around 5 days of illness. Of those with abnormal LS or CS strain, 50% normalized in ≤1 week, 95% within 50 days. Adverse CV outcomes occurred in 121 (35%) patients. Patients with adverse outcomes were older (p=0.003), more likely to have an underlying metabolic/genetic disorder (p=0.015), abnormal troponin (p<0.001), and higher C-reactive protein (CPR) at admission (p<0.001). They also had higher indexed LV end-diastolic volume (p<0.001) and mass (p=0.015), worse EF (p<0.001), worse LS (p=0.002), and worse CS (p=0.001). When adjusting for days of illness, age, gender, race, obesity, comorbidities, SARS-CoV-2 positivity, CRP, and abnormal troponin at admission, LS Z-score (adjusted OR 1.24 [95% CI 1.03,1.49], AUC 0.754 and longitudinal early diastolic strain rate (LEDSR; adjusted OR 1.98 [IQR 1.18, 3.33], AUC 0.760) at admission were independently associated with adverse CV outcomes. Conclusion: Almost half of the MISC patients had abnormal LS or CS at admission, but the majority recovered quickly. LS and LEDSR at admission were independently associated with adverse CV outcomes. These data may help in early characterization, risk stratification, and prognostication in patients with MISC.