Inhibitor of differentiation 4 (Id4) plays an important role in tumorigenesis, but its role in cancer chemoresistance remains unclear. Our study showed that Id4 expression in cisplatin-resistant A549/DDP cells was higher than that in parental A549 cells. Moreover, overexpression of Id4 in A549 cells results in cisplatin resistance and apoptosis inhibition, while increasing the IC50 for cisplatin through activation of phospho-p38 MAPK. However, Id4 knockdown in A549/DDP cells was shown to resensitize A549/DDP cells to cisplatin and induce apoptosis, as well as decrease the IC50 for cisplatin through inactivation of phospho-p38 MAPK. In addition, a p38 MAPK inhibitor (SB202190) could partly reverse both Id4-reduced apoptosis and Id4-induced cisplatin resistance. These results suggest that Id4 inhibits cisplatin-induced apoptosis in human lung adenocarcinoma, partially through activation of the p38 MAPK pathway. Our research indicates that Id4 may be a new target for non-small-cell lung cancer treatment.