Accumulating evidence demonstrated that long non-coding RNAs (lncRNAs) derived from exosomes had the potential to be diagnostic markers for lung cancer. However, the diagnostic value of lncRNAs from epithelial cell adhesion molecule (EpCAM)-positive exosomes remains unclear. In the study, serum EpCAM-positive exosomes were isolated with magnetic beads, and their role in lung cancer was investigated in vitro and in vivo. The copy numbers of lncRNAs RP11-77G23.5 and PHEX-AS1 in EpCAM-specific exosomes were quantified by droplet digital PCR (ddPCR). The diagnostic value of RP11-77G23.5 and PHEX-AS1 was tested in the training cohort and verified in the validation cohort. We found that EpCAM-specific exosomes could promote lung cancer development in vitro and in vivo. RP11-77G23.5 and PHEX-AS1 were significantly elevated in EpCAM-specific exosomes from lung cancer patients and could distinguish malignant from benign lung tumors. The amounts of RP11-77G23.5 were statistically higher in the subtype of lung adenocarcinoma (LUAC) than that of lung squamous cell carcinoma (LUSC), showing its capability to subtype LUAC and LUSC, while PHEX-AS1 exhibited distinct expression signatures between lower and higher tumor stages, and without and with distant metastasis, indicating its association with lung cancer progression. In conclusion, the EpCAM-specific exosomal lncRNAs RP11-77G23.5 and PHEX-AS1 may be promising diagnostic biomarkers for lung cancer. KEY MESSAGES: Serum EpCAM-positive exosomes promote lung cancer development in vitro and in vivo. Two EpCAM-specific exosomal lncRNAs can be simultaneously detected by RT-ddPCR. EpCAM-specific exosomal RP11-77G23.5 has the potential to subtype LUAC and LUSC. EpCAM-specific exosomal PHEX-AS1 is associated with lung cancer progression.