COVID-19 severity is correlated with granulocyte macrophage colony-stimulating factor (GM-CSF) and C reactive protein (CRP) levels. In the phase three LIVE-AIR trial, lenzilumab an anti-GM-CSF monoclonal antibody, improved the likelihood of survival without ventilation (SWOV) in COVID-19, with the greatest effect in participants having baseline CRP below a median of 79 mg/L. Herein, the utility of baseline CRP to guide lenzilumab treatment was assessed. A subanalysis of the randomised, blinded, controlled, LIVE-AIR trial in which lenzilumab or placebo was administered on day 0 and participants were followed through Day 28. Hospitalised COVID-19 participants (N=520) with SpO2 ≤94% on room air or requiring supplemental oxygen but not invasive mechanical ventilation. Lenzilumab (1800 mg; three divided doses, q8h, within 24 hours) or placebo infusion alongside corticosteroid and remdesivir treatments. The primary endpoint was the time-to-event analysis difference in SWOV through day 28 between lenzilumab and placebo treatments, stratified by baseline CRP. SWOV was achieved in 152 (90%; 95% CI 85 to 94) lenzilumab and 144 (79%; 72 to 84) placebo-treated participants with baseline CRP <150 mg/L (HR: 2.54; 95% CI 1.46 to 4.41; p=0.0009) but not with CRP ≥150 mg/L (HR: 1.04; 95% CI 0.51 to 2.14; p=0.9058). A statistically significant interaction between CRP and lenzilumab treatment was observed (p=0.044). Grade ≥3 adverse events with lenzilumab were comparable to placebo in both CRP strata. No treatment-emergent serious adverse events were attributed to lenzilumab. Hospitalised hypoxemic patients with COVID-19 with baseline CRP <150 mg/L derived the greatest clinical benefit from treatment with lenzilumab. NCT04351152; ClinicalTrials.gov.