SARS-CoV2-induced direct cytopathic effects against type II pneumocytes are suspected to play a role in mediating and perpetuating lung damage. The aim of this study was to evaluate serum KL-6 behavior in COVID-19 patients to investigate its potential role in predicting clinical course. Sixty patients (median age IQR, 65 (52–69), 43 males), hospitalized for COVID-19 at Siena COVID Unit University Hospital, were prospectively enrolled. Twenty-six patients were selected (median age IQR, 63 (55–71), 16 males); all of them underwent follow-up evaluations, including clinical, radiological, functional, and serum KL-6 assessments, after 6 (t1) and 9 (t2) months from hospital discharge. At t0, KL-6 concentrations were significantly higher than those at t1 (760 (311–1218) vs. 309 (210–408) p = 0.0208) and t2 (760 (311–1218) vs 324 (279–458), p = 0.0365). At t0, KL-6 concentrations were increased in patients with fibrotic lung alterations than in non-fibrotic group (755 (370–1023) vs. 305 (225–608), p = 0.0225). Area under the receiver operating curve (AUROC) analysis showed that basal KL-6 levels showed good accuracy in discriminating patients with fibrotic sequelae radiologically documented (AUC 85%, p = 0.0404). KL-6 concentrations in patients with fibrotic involvement were significantly reduced at t1 (755 (370–1023) vs. 290 (197–521), p = 0.0366) and t2 (755 (370–1023) vs. 318 (173–435), p = 0.0490). Serum concentrations of KL-6 in hospitalized COVID-19 patients may contribute to identify severe patients requiring mechanical ventilation and to predict those who will develop pulmonary fibrotic sequelae in the follow-up.