A major part of non-small cell lung cancer (NSCLC) patients treated with mono- or multimodal concept develop therapy resistance. Despite the abundance of biomarkers investigated in the past, there is still a need for valid NSCLC biomarkers. Glycodelin, an immunosuppressive endometrial protein, has been shown to be also expressed in NSCLC. Here, we investigated its potential as a biomarker in metastatic and advanced stage NSCLC. Glycodelin gene and protein expression were measured in 28 therapy-naïve resected tumors as well as in corresponding brain (n = 16) and adrenal gland (n = 12) metastasis by qPCR and IHC. Moreover, we correlated glycodelin gene expression of cryoconserved therapy-naïve biopsies (n = 55) of advanced stage patients with glycodelin serum concentrations and patient survival. Using follow-up samples of the patients, we monitored glycodelin serum concentrations during therapy. Glycodelin expression correlated between primary tumor and distant metastases within the same patients. The gene expression of glycodelin in therapy-naïve biopsies also correlated with the serum concentrations of the patients (r = 0.60). Patients with elevated serum concentrations showed a tendency in lower overall survival (p = 0.088) and measuring of glycodelin indicated a progression of the disease earlier compared to clinical diagnostic. Taken together, we demonstrate that glycodelin is a promising prognostic and follow-up biomarker for metastatic and advanced NSCLC.