Using apoptosis-inducing factor protein as bait in a yeast hybrid assay to screen protein libraries, we identified three proteins that interacted with apoptosis-inducing factor: human homolog of yeast Rad23 protein A (hHR23A), microsomal glutathione S-transferase and caspase-14 (casp-14). In this study, we investigated the expression and function of casp-14 in lung adenocarcinomas (LADC). Our results showed that monoclonal antibodies were specific to casp-14, and that casp-14 was highly expressed in LADC. Casp-14 overexpression correlated with tumor stage, cell differentiation and lymphovascular involvement, suggesting that casp-14 was associated with tumor cell growth and metastatic potential. In vitro, casp-14 interacted with apoptosis-inducing factor, and silencing of casp-14 expression reduced cisplatin resistance. Our data suggest that casp-14 is an anti-apoptotic protein targeting apoptosis-inducing factor and increases cisplatin resistance in LADC cells.