Objective To explore the synergistic apoptosis-promoting effect of fenretinide (N-\[4-hydroxyphenyl\] retinamide, 4-HPR, a synthetic retinoic acid) with bortezomib in non-small cell lung cancer (NSCLC) A549 cells. Methods NSCLC A549 cells were treated with 4-HPR and bortezomib alone or in combination at different concentrations (2.5,5,10 and 20 μmol/L for 4-HPR; 0.1,0.2,0.4 and 0.8 μmol/L for bortezomib) for 24 h. MTT assay was performed to detect cell growth inhibition. Propidium iodide (PI) staining and flow cytometry were performed to analyze cell cycle. Annexin Ⅴ-FITC and PI double staining was performed to detect apoptosis. Real-time quantitative PCR and Western blotting analysis were performed to examine the expression of endoplasmic reticulum stress protein CHOP. Results 4-HPR or bortezomib alone inhibited the cell proliferation in a dose-dependent manner, and combined treatment with both 4-HPR and bortezomib showed significantly a stronger anti-proliferative effect. Cell cycle analysis showed that the combination of the two drugs caused cell cycle arrest in the G0/G1 phase, with S phase cells significantly reduced. Compared with 4-HPR or bortezomib used alone, combination of both significantly enhanced the apoptosis of A549 cells, accompanied by enhanced expression of CHOP mRNA and protein, an endoplasmic reticulum stress marker. Conclusion Combination of 4-HPR and bortezomib can promote apoptosis in lung cancer A549 cells, which provides an experimental basis for their combination treatment of lung cancer.