Humanized Virus Suppressing Factor-variant 13 (hzVSF-v13), a monoclonal IgG4 antibody against vimentin, was investigated in moderate to severe COVID-19 pneumonia through a Phase II study. Patients were randomized to two different IV doses of the test drug or saline with standard of care. Overall, 64 patients were recruited, and 62 entered the efficacy assessment in the full analysis set. Primary endpoint: The clinical failure rate at day 28 was 15.8% for placebo, 9.1% for low-dose hzVSF-v13 and 9.5% for high-dose hzVSF-v13 (not significant). A trend toward better efficacy was shown in several secondary endpoints, with statistical significance between low-dose hzVSF-v13 and placebo in terms of the rate of improved patients on the ordinal scale for clinical improvement (OSCI): 90.0% vs. 52.63% (p = 0.0116). In the severe stratum, the results of low-dose hzVSF-v13 vs. placebo were 90.0% and 22.2% for OSCI (p = 0.0092), 9 days and 14 days for time to discontinuation of oxygen therapy (p = 0.0308), 10 days and 15 days for both time to clinical improvement (TTCI) and time to recovery (TTR) and p = 0.0446 for both TTCI and TTR. Change from baseline of NEWS2 score at day 28 was −3.4 vs. + 0.4 (p = 0.0441). The results propose hzVSF-v13 as a candidate in the treatment of severe COVID-19.