Abstract Background Host-response biomarkers to differentiate bacterial from viral etiology in children with respiratory infections have shown high accuracies, but are understudied in Mycoplasma pneumoniae (Mp) infections. Methods We compared BV scores (0–34 indicating viral etiology, and 66–100 indicating bacterial etiology), tumor necrosis factor–related apoptosis-inducing ligand (TRAIL; pg/mL), interferon-γ inducible protein 10 (IP-10; pg/mL), and C-reactive protein (CRP; mg/L) serum levels between Mp-positive (Mp+) and Mp-negative (Mp−) community-acquired pneumonia (CAP) patients. We performed receiver operating characteristic (ROC) curve analyses for clinical features and biomarkers. Results Of 80 CAP patients (median age, 6.3 years; 57.5% male), 26 had Mp+CAP. In Mp+CAP patients, compared to Mp−CAP patients, BV scores were lower (14.0 3.0–27.8 vs 54.0 12.0–84.8; P = .0008), TRAIL levels were higher (86.5 67.4–123.0 vs 65.5 42.5–103.9; P = .025), CRP levels were lower (12.9 4.0–22.3 vs 36.7 13.0–132.8; P = .0019), and IP-10 levels were comparable (366.0 150.2–603.8 vs 331.0 154.3–878.8; P = .73) (all median interquartile range). ROC analyses yielded a comparable discriminatory accuracy for the combination of age, fever duration, and duration of respiratory symptoms, with either procalcitonin or BV score (area under the ROC curve, 0.87 vs 0.86; P = .94). Conclusions Children with Mp+CAP have atypically low, viral levels of the BV score, underscoring the complementary role of microbiological testing.