Objective To observe the expression levels of growth differentiation factor-15 (GDF-15) and interleukin-12 (IL-12) in the serum and their correlation with pulmonary infection after mechanical ventilation in the elderly patients in intensive care unit (ICU). Methods From July 2016 to August 2019,169 elderly patients who underwent mechanical ventilation in the ICU of the First Affiliated Hospital of Harbin Medical University were selected as the observation group, among whom 71 had pulmonary infection and 98 did not; 102 elderly people without lung disease were selected as the control group. The expression levels of GDF-15 and IL-12 in serum were measured and compared by enzyme-linked immunosorbent assay (ELISA). SPSS statistics 21.0 was used for data analysis. Logistic analyses were performed for the risk factors of pulmonary infection after mechanical ventilation, and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic values of serum GDF-15 and IL-12 expression levels in pulmonary infection. Results The expression levels of serum GDF-15 and IL-12 were (862.08±263.33) pg/ml and (70.88±14.61) pg/ml in the group without pulmonary infection and(1 431.42±310.50) pg/ml,(93.02±20.05) pg/ml in the group with pulmonary, which were all higher than those in the control group [(564.98±133.38), (46.90±20.14) pg/ml; q=12.443,13.097,33.211,23.052; P<0.05]. The expression levels of GDF-15 and IL-12 in the group with pulmonary infection were higher than those in the group without (q=21.643, 10.975; P<0.05). Logistic regression analysis showed that the high levels of serum GDF-15 and IL-12 were the risk factors of pulmonary infection after mechanical ventilation. In the diagnosis of pulmonary infection after mechanical ventilation, the area under ROC curves (AUC) of serum GDF-15 was 0.895 with a sensitivity of 76.1% and a specificity of 95.9%, AUC of serum IL-12 was 0.747 with a sensitivity of 54.9% and a specificity of 85.7%, and AUC for them in combination was 0.940 with a sensitivity of 81.7% and a specificity of 98.0%. Conclusion GDF-15 and IL-12 are highly expressed in the serum of the elderly patients with pulmonary infection after mechanical ventilation in ICU. The combined detection of serum GDF-15 and IL-12 has a high diagnostic value for pulmonary infection after mechanical ventilation in the elderly patients.