In this single-center, retrospective cohort analysis of hospitalized coronavirus disease 2019 (COVID-19) patients, we investigate whether inflammatory biomarker levels predict respiratory decline in patients who initially present with stable disease. Examination of C-reactive protein (CRP) trends reveals that a rapid rise in CRP levels precedes respiratory deterioration and intubation, although CRP levels plateau in patients who remain stable. Increasing CRP during the first 48 h of hospitalization is a better predictor (with higher sensitivity) of respiratory decline than initial CRP levels or ROX indices (a physiological score of respiratory function). CRP, the proinflammatory cytokine interleukin-6 (IL-6), and physiological measures of hypoxemic respiratory failure are correlated, which suggests a mechanistic link. Our work shows that rising CRP predicts subsequent respiratory deterioration in COVID-19 and may suggest mechanistic insight and a potential role for targeted immunomodulation in a subset of patients early during hospitalization. Display omitted Rising CRP levels predict intubation in COVID-19 inpatients stable at admissionEarly CRP trend outperforms initial CRP level in prediction of respiratory failureCRP trend outperforms a physiological index (ROX) in prediction of respiratory failureCRP and IL-6 levels correlate with each other and with hypoxemia (PaO2/FiO2) Mueller et al. demonstrate in hospitalized COVID-19 patients that trending C-reactive protein (CRP), an inflammatory biomarker, is a simple and accessible strategy for predicting respiratory deterioration. An early rise in CRP predicts intubation, and CRP levels correlate with IL-6 levels and physiological measures of hypoxemic respiratory failure.