Irinotecan (CTP-11) is a topoisomerase I inhibitor used in the treatment of colorectal cancer and non-small cell lung cancer (NSCLC). Despite an initial response to therapy, resistance to irinotecan reduces its efficacy. We isolated irinotecan-resistant human NSCLC A549 cells, termed A549/CTP-11R cells. A549/CTP-11R cells were resistant to irinotecan, as well as paclitaxel, gemcitabine and carboplatin. Curcumin, a nuclear factor-κB (NF-κB) inhibitor, increased the sensitivity to irinotecan of A549/CTP-11R cells. The expression level of Bcl-XL and X-linked inhibitor of apoptosis protein, target genes of NF-κB, in A549/CTP-11R cells was higher than that in A549 cells. Our result suggests that the addition of curcumin to irinotecan reverses irinotecan resistance in NSCLC.