Lung adenocarcinoma (LUAD) is the predominant type of non-small lung cancer (NSCLC) with strong invasive ability and poor prognosis. The drug resistance related genes are potentially associated with prognosis of LUAD. Our research aimed to identify the drug resistance related genes and explore their potential prognostic value in LUAD patients. The data used in this study were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Firstly, we screened drug resistance related genes in LUAD by differential gene analysis, univariate Cox regression and drug sensitivity analyses. Subsequently, we constructed a risk score model using LASSO Cox regression analysis, and verified whether the risk score can predict the survival of LUAD patients independent of other factors. Moreover, we explored the immune infiltration of 22 immune cells between high-risk and low-risk patients. Totally 10 drug-resistance positively related genes (PLEK2, TFAP2A, KIF20A, S100P, GDF15, HSPB8, SASH1, WASF3, LAMA3 and TCN1) were identified in LUAD. The risk score model of LUAD constructed with these 10 genes could reliably predict the prognosis of LUAD patients. 18 pathways were significantly activated in high-risk group compared with low-risk group. In addition, the infiltration proportion of multiple immune cells was significantly different between high-risk and low-risk groups, and the proportion of M1 phagocytes was significantly higher in the high-risk group compared with the low-risk group. The drug resistance related genes (PLEK2, TFAP2A, KIF20A, S100P, GDF15, HSPB8, SASH1, WASF3, LAMA3 and TCN1) could predict the prognosis of LUAD patients. Clarifying the roles and mechanisms of these 10 genes in regulating drug resistance in LUAD will help to improve individualized clinical treatment protocols and predict patient sensitivity to treatment.