BACKGROUND: Zinc is undergoing evaluation as an inexpensive therapeutic adjuvant for severe pediatric pneumonia. OBJECTIVE: We explored the effect of etiology on the treatment effect of zinc in young children hospitalized for severe pneumonia. DESIGN: We analyzed data from a randomized, double-blind, placebo-controlled clinical trial conducted at the Christian Medical College Hospital, a teaching hospital in Tamilnadu, India. Children aged 2-23 mo (n = 299) were randomly assigned to receive a 10-mg tablet of zinc sulfate or placebo twice a day during hospitalization. The primary outcomes were length of hospitalization and time to resolution of severe pneumonia stratified by etiologic classification on the basis of serum C-reactive protein (CRP) concentrations at admission. RESULTS: CRP concentrations were available for 295 (98.7%) of the enrolled cases. Of these 295 cases, 223 (75.6%) were classified as suspected nonbacterial pneumonias (CRP concentrations <=40 mg/L). Etiology modified the treatment effect of zinc on the length of the hospital stay hazard ratio (HR) for interaction term: 0.52; 95% CI: 0.31, 0.91; P = 0.022. In the 72 suspected bacterial cases (CRP concentrations >40 mg/L), the median length of hospitalization was almost equal to20 h longer in the zinc-supplemented group than in the placebo group (87.3 and 68.3 h, respectively; HR: 0.56; 95% CI: 0.34, 0.93; P = 0.025). The treatment effect was not modified in the suspected nonbacterial cases of pneumonia. CONCLUSIONS: Our results suggest that the treatment effect of zinc for severe pediatric pneumonia may be modified by bacterial infection. Further studies are required to develop appropriate recommendations for the use of zinc in the treatment of severe pneumonia. This trial was registered at clinicaltrials.gov as NCT00198666.