Syndrome of inappropriate antidiuresis (SIAD) in cancer is the main cause of hyponatremia and is associated with poorer survival, hospitalization and health costs in lung cancer (LC) patients (pts). Micro-RNAs (miRNAs) represent promising biomarkers with therapeutic potential. Our retrospective study aims to assess a miRNA signature to discriminate hyponatremia and predict clinical outcome in LC pts. We performed a miRNA sequencing in 20 FFPE tumor samples of 10 eunatremic and 10 hyponatremia-developing LC pts through Illumina NextSeq500 sequencer. Pts’ records were reviewed to assess outcome measures. The differential miRNA expression profile was analyzed between the two groups. miRNAs with |log2(fold change)|>0.58 and p<0.05 were considered statistically significant and correlated with survival outcomes, relapse-free survival (RFS), progression-free survival (PFS) and overall survival (OS), using three Cox multivariate regression models. 12 miRNAs were differentially expressed at diagnosis between hypo- and eunatremic pts at univariate analysis (p<0.05). At multivariate analysis, miR-147b-3p (median expression 10.8 vs 92.6, p=0.025), miR-147b-5p (2.6 vs 15.9, p=0.002), miR-937-3p (3.4 vs 14.6, p=0.039) and miR-146a-5p (6106.6 vs 16601.4, p=0.035) were significantly downregulated in hypo- vs eunatremic pts. Similarly, miR-539-3p (3.4 vs 14.9, p=0.083) and miR-625-3p (97.8 vs 308.9, p=0.061) showed a trend towards significance for downregulation. Contrarily, miR-190a-5p (304.2 vs 179.5, p=0.006) and miR-32-3p (7 vs 3, p=0.017) were upregulated in the hyponatremic vs control group. Looking at survival outcomes, the upregulation of miR-937-3p (p=0.042), miR-190a-5p (p=0.001) and miR-9-3p (p=0.035) was associated with worse OS, while the upregulation of miR-32-3p was associated with improved OS (p=0.010) and RFS (p=0.064). Our results reveal new insights into the role of vasopressin pathways in LC. These miRNAs appear as valuable early predictors of hyponatremia and their expression is associated with a significant impact on pts’ survival. Further investigations, including our prospective study, are warranted to provide advances in SIAD management.