The role of the tumour microenvironment is recognized as playing a significant role in cancer progression and patient survival. Prognostic indices derived from peripheral blood components are employed as an indicator of tumour microenvironment, and have shown prognostic utility in a number of solid tumors. Within non-small cell lung cancer (NSCLC), haematologically derived prognostic indices have shown an association with outcome in advanced disease treated with immune checkpoint inhibitors and in early-stage resected tumors, but few studies have sought to evaluate the predictive ability of prognostic markers in advanced NSCLC on targeted therapy, aside from a recognized association between elevated lactose dehydrogenase (LDH) and poor prognosis in this population. In response, we aimed to evaluate the potential of an innovative and inexpensive marker, the systemic immune-inflammatory index (SII), as a prognostic tool in metastatic EGFR-mutant NSCLC receiving first-line tyrosine kinase inhibitor therapy (EGFR-TKI) in the real-world setting. Alberta patients with a diagnosis of de novo metastatic EGFR-mutant NSCLC and receiving frontline EGFR-TKI between 2010 and 2018 were identified, and their demographic, clinical, treatment and outcome data were extracted from the institutional Glans-Look Lung Cancer Database. SII was calculated as pre-treatment (≤ 30 days prior to EGFR-TKI initiation) platelet count multiplied by neutrophil count, divided by lymphocyte count. Receiver operator characteristic (ROC) curves were constructed to identify optimal cut-off points for SII, and patients were stratified by this factor. Univariate analysis was performed to assess differences between high and low SII groups, and Kaplan-Meier survival analysis employing the log-rank test was conducted to estimate overall survival (OS) and progression-free survival (PFS). 220 patients were identified. Median age was 65.6 years, 59% never-smokers, 64% female, 85% Exon 19 or 21 mutation. 75% were treated with gefitinib, 25% afatinib in the first-line setting. An optimal cut-off value for SII of 1200 was identified using ROC and applied; 55% of patients had ‘high’ SII. Compared to patients with low-SII, patients with high-SII had significantly shorter PFS (15.6 vs 10.8 months, p < 0.001) and OS (30.4 vs 20.1 months, p < 0.001). Low-SII and high-SII patients were clinicopathologically similar, apart from an association between high-SII and elevated lactate dehydrogenase (LDH). LDH was elevated, according to laboratory derived cut-off values (> 235 U/L), in 56% of patients; we combined LDH value with SII to create a risk factor count, identifying the number of elevated markers (LDH and SII) present (none, one or two). Patients were then stratified according to number of risk factors, and OS and PFS investigated: 26% of patients had no elevated markers, 37% one elevated marker, 37% two elevated markers, with median PFS of 15.7, 13.9, 9.5 months, respectively (p< 0.001), and median OS of 32.8, 26.3, and 17.6 months, respectively (p<0.001). This study demonstrates that elevated SII is a strong prognostic indicator, associated with shortened PFS and reduced OS in metastatic EGFR-mutant NSCLC on first-line EGFR-TKI. Enumerating the presence of elevated SII and LDH can create a simple and cost-effective indicator of outcome within this real-world population.