Non-small cell lung cancer (NSCLC) is one of the most common malignant tumours in the Western world and is associated with a poor prognosis. Biomarkers predicting prognosis and therapeutic effects are highly required, and cell-free DNA (cfDNA) may be a feasible option. Genetic mutations can be analysed in plasma and may increase the scientific use of such measurements. In the present study, we investigated: i) the dynamics of cfDNA and plasma mutated KRAS (pmKRAS) during the treatment of patients with advanced NSCLC; and ii) the prognostic value of baseline cfDNA and pmKRAS. Sixty-nine patients were included in a prospective biomarker trial. Inclusion criteria included advanced NSCLC, candidate for first-line treatment, no previous cancer within the five years prior to this study. Blood samples were drawn at baseline, day 8 and at progression. Analyses of cfDNA and KRAS mutations in plasma were performed using an in-house qPCR assay. Evaluation of the treatment effect and status at follow-up was performed according to RECIST 1.1. The median levels of cfDNA were significantly higher at progression (9,250 alleles/ml) than at baseline (5,450 alleles/ml). Overall survival and progression-free survival were both significantly shorter in patients with high levels of cfDNA (above the 75th percentile) compared to lower levels. Only few patients harboured KRAS mutations in plasma. Two patients had no KRAS mutations in plasma at baseline, but mutations appeared in the subsequent blood samples. High baseline levels of cfDNA indicate a poor prognosis. The level changes during the treatment course with a significant increase at progression, suggesting a possible predictive value of cfDNA. The plasma KRAS status may change during treatment with potential implications for treatment selection.