To identify specific symptoms, physical examination findings, and laboratory findings that are more indicative of patients with multisystem inflammatory syndrome in children (MIS-C), as opposed to other febrile illnesses.Two cohorts of patients ≥12 months were used in this study. Included in the first cohort were 44 patients who were diagnosed and treated for MIS-C at a large urban children’s hospital in New York. Included in the second cohort were 181 patients who presented for evaluation of a febrile illness to a hospital-affiliated primary care pediatric clinic, 23 of whom were also evaluated in the emergency department.This study was performed via a retrospective chart review. The inpatient cohort was selected from the New York City Department of Health’s list of possible MIS-C cases from April 16 to June 10, 2020. Patients with MIS-C were defined as those who received treatment with intravenous immunoglobulin and corticosteroids in concordance with recommendations by rheumatology and infectious disease specialists. Patients whose cases were more consistent with Kawasaki disease as per American Heart Association 2017 guidelines and clinical judgement were excluded. Outpatient cases were selected by using a list of all patients who presented for an acute febrile illness during the same time period. Fever was defined as a temperature ≥38°C, but, if not documented or if <38°C, the fever height was recorded as “subjective.” Because most outpatients were evaluated via telehealth, laboratory testing was compared only between inpatients and patients evaluated in the emergency department. Demographics, laboratory values, physical examination findings, and symptoms were compared among the 2 groups.Patients diagnosed with MIS-C, compared with those diagnosed with other febrile illnesses were found to exhibit the following: greater median age (8.2 years versus 3.5 years; P < .001), greater maximum temperature (40.0°C vs 38.9°C; P < .001), and longer duration of fever before presentation (5 days versus 2 days; P < .001). Laboratory evaluation among patients with MIS-C versus those who presented to the ED for fever revealed more significant lymphopenia (absolute lymphocyte count: 900 cells per µL [490–1700] vs 2860 cells per µL [1900–5400], respectively; P < .001), a greater neutrophil percentage (80.5% [71.6–85.7] vs 40.1% [19–60]; P < .001), and a lower initial platelet count (179 000 per µL [130 000–243 000] vs 224 000 per µL [195 000–308 000]; P < .05). Patients with MIS-C were also found to have statistically significant elevated levels of C-reactive protein (164 mg/L [52–250]) and N-terminal brain natriuretic peptide (6700 pg/µL [2509–25 550]), but these values were only available in 14 inpatients and 9 outpatients. Clinical symptoms, including abdominal pain, vomiting, mucosal irritation, neck pain or stiffness, and rash, all correlated with MIS-C (P < .05)In comparing patients with MIS-C to patients with other febrile illnesses, a particular set of symptoms, laboratory values, and physical findings were identified.The diagnosis and management of MIS-C has evolved over the course of the pandemic, and the clinical presentation can be variable. With this study, the authors help to highlight clinical findings in patients with a diagnosis more consistent with MIS-C, as opposed to other febrile illnesses. When evaluating patients with fever, it is important to be aware of these possible MIS-C “red flags” but equally important to have a broad differential diagnosis. Appropriately diagnosing patients with MIS-C is imperative because current treatment recommendations include immunomodulation with corticosteroids and immunoglobulin. Such treatment may be undesirable in patients with overlap symptoms secondary to other systemic diseases (ie, sepsis or malignancy).