Background: Systemic inflammation has been linked to incidence, progression, and poor outcomes in various cancers including non-small cell lung carcinoma (NSCLC). High-sensitivity CRP (hs-CRP) assays, generally used to assess cardiovascular risk, have rarely been evaluated in lung cancer studies. This study aimed to evaluate if baseline and on-treatment measurements of serum hs-CRP could provide prognostic and predictive information for patients with metastatic NSCLC treated with chemotherapy. Methods: In this single institutional prospective study 85 patients with metastatic NSCLC without targetable alterations who were treated with chemotherapy were included between 1st January 2020 and 31st December 2020, with a minimum follow-up duration of 6 months. Patients with coronary artery disease, active infections, autoimmune conditions, and chronic liver disease were excluded. Measurements of hs-CRP for all patients were done at baseline and every 12 weeks while on treatment. Patients were grouped by changes in hs-CRP levels compared to baseline levels as reduction (≥ 20% decline), and non-reduction (< 20% decline) to assess association with radiologic response and progression- free survival (PFS). Results: Pre-treatment hs-CRP values were elevated for the majority (92.9% patients with ≥ 1 mg/L, 70.6% with ≥ 3 mg/L, and 42.3% with ≥ 10 mg/dL). No significant association was detected between the pre-treatment hs-CRP value and the number of metastatic sites (P = 0.4), histology (P = 0.3), or smoking status (P = 0.7). At a median follow-up of 13.7 months, the median PFS was 7.8 months (95% confidence interval [CI] 5.3 - 10.3). Patients with hs-CRP ≥10 mg/L had shorter PFS than those with hs-CRP < 10 mg/L (Median PFS 7.5 months [95% CI 4.9 - 10] vs. 8.4 months [95% CI 0.1 - 17.4]; hazard ratio [HR] 1.8, 95% CI 1-3.4, P = 0.04). hs-CRP reduction (≥20% decline) after 12 weeks of treatment initiation predicted radiological response (P < 0.001). Median PFS was 14.7 months (95% CI 7.4 – 22.1) in patients who demonstrated hs-CRP reduction (≥20% decline) at 12 weeks compared to 3.1 months (95% CI 2.3 – 3.9) in patients who did not (HR 0.17, 95% CI 0.08 - 0.33, P < 0.001). Conclusions: Elevated hs-CRP at baseline was found to be a poor prognostic factor, while hs-CRP reduction by 20% or more on treatment predicted radiologic response and longer PFS in metastatic NSCLC patients treated with chemotherapy. Our findings of potential predictive and prognostic value of hs-CRP in metastatic NSCLC warrant validation in larger prospective studies.