Krebs von den Lungen-6 (KL-6), expressed by damaged type II pneumocytes, is useful in the diagnosis and severity assessment of many diffuse interstitial lung diseases. The objective of our study was to determine the prognostic value of the initial KL-6 plasma level in COVID-19 pneumonia. Methods All patients hospitalized for a suspected COVID-19 pneumonia between March and May 2020 in our Chest department of a French university hospital were included. KL-6 serum concentrations were measured within 72 h of diagnostic suspicion by chemiluminescence enzyme immunoassay Survival analysis was performed using a Cox regression and modeled by a Kaplan-Meier curve. Results Sixty-six COVID-19 patients (average age = 64±14 years ,71.2% males) with KL-6 serum measurement were included. Median KL-6 serum concentration was 409±312 U/mL. KL-6 was significantly higher in men (p=0.003), elders (p=0.0001) and in patients with greater Charlson’s score (p=0.002). Higher KL-6 concentration was significantly associated with in-hospital mortality (HR: 8.66; 95% CI:1.1-69.2, p=0.014), radiological extension of lesions on chest CT scan (p=0.004) and higher WHO severity score (p=0.042), but not with admission in intensive care unit. In 9 (14%) non-surviving COVID-19 patients, KL-6 serum concentration increased whereas it remained stable or decreased in survivors. At 3 months follow-up (n=48), DLCO was negatively correlated with the initial KL-6 value (r=0.47, p=0.001), while FVC, FEV1 and MRC score were not. Conclusion Initial KL-6 serum concentration is significantly associated with in-hospital mortality, unfavorable outcome, and persistent impairment of DLCO at 3 months. Initial KL-6 plasma determination appears as a prognostic biomarker in COVID-19 pneumonia.