The optimal management strategy for newly diagnosed pulmonary ground-glass nodules (GGNs) with suspected inflammatory etiology remains controversial in clinical practice. Empirical anti-inflammatory therapy is commonly used, but its efficacy compared with that of follow-up observation lacks high-quality evidence. Therefore, this study aims to compare the effectiveness of empirical anti-infective therapy and follow-up observation for pulmonary GGNs in real-world settings.This study intends to include 254 participants with newly discovered pulmonary ground-glass opacities (GGOs) suspected to be related to inflammation but without current radiographic features suggestive of malignancy. Antibiotics will be recommended when the doctor considers the GGOs may be infection-related. Upon enrollment, all participants will be assessed with the Self-Rating Anxiety Scale (SAS) and divided into either the intervention or observation group. A repeat CT scan and SAS assessment will be conducted with all participants after 1 month ( ± 2 weeks) following the initial discovery of the GGOs. The primary outcome is the participants' response rate at the first follow-up CT. The secondary outcome is the GGO response rate and total scores of SAS at 1 month after enrollment. A non-inferiority test will be conducted to compare the outcomes between the two groups.To date, the efficacy and necessity of using antibiotics for GGOs suspected to be inflammatory upon primary CT screening remain controversial. This protocol describes the rationale and methodology to address this unmet clinical need using real-world data, aiming to bridge the gap between clinical guidelines and real-world practice. Trial Registration: ChiCTR2200056975.© 2024 The Author(s). Health Science Reports published by Wiley Periodicals LLC.