Background:　Drug-induced　immune　hemolytic　anemia　(DIIHA)　is　a　rare　but　potentially　life-threatening　drug-related　complication.　There　are　no　previous　reports　of　pemetrexed　plus　cisplatin　as　first-line　chemotherapy　for　non-small　cell　lung　cancer,　resulting　in　DIIHA.　Case　presentation:　In　this　report,　a　patient　with　advanced-stage　lung　adenocarcinoma　developed　severe　immune　hemolytic　anemia　21　days　after　pemetrexed　plus　cisplatin　chemotherapy.　Laboratory　findings　showed　severe　hemolysis,　including　a　rapid　decrease　in　hemoglobin　(HGB)　and　an　elevated　level　of　reticulocytes　(Rets),　indirect　bilirubin　(IBIL),　and　lactate　dehydrogenase　(LDH).　A　workup　for　the　possibility　of　DIIHA　was　performed,　including　a　direct　antiglobulin　test　(DAT),　a　test　in　the　presence　of　the　soluble　drug,　and　a　drug-treated　red　blood　cell　(RBC)　test.　It　showed　a　strongly　positive　(3+)　result　for　anti-C3d　but　not　for　anti-immunoglobin　G　(IgG)　in　DAT.　Enzyme-treated　RBCs　reacted　weakly　with　the　patient＇s　serum　and　pemetrexed　when　complement　was　added.　In　addition,　the　patient＇s　serum　and　normal　sera　were　reactive　with　cisplatin-treated　RBCs.　However,　eluates　from　the　patient＇s　RBCs　and　diluted　normal　sera　were　non-reactive　with　cisplatin-coated　RBCs.　Untreated　and　enzyme-treated　RBCs　reacted　with　the　patient＇s　serum　in　the　presence　of　soluble　cisplatin.　In　vitro　serological　tests　suggested　that　complement-dependent　pemetrexed　antibodies　and　cisplatin-associated　non-immunologic　protein　adsorption　(NIPA)　might　combine　to　cause　immune　hemolytic　anemia.　The　patient＇s　anemia　gradually　recovered　when　pemetrexed　and　cisplatin　were　discontinued.　Conclusion:　This　rare　case　demonstrated　that　complement-dependent　pemetrexed　antibodies　and　cisplatin-associated　NIPA　might　occur　simultaneously　in　a　patient　with　DIIHA.　Copyright　©　2022　Lu,　Wang,　Wang,　Zhang,　Zhao,　Liu,　He,　Liu,　Chang,　Cao　and　Wang.