OBJECTIVE To investigate the pharmacodynamics of chronopharmaceutical drug delivery of erlotinib in lung cancer model nude mice and its potential mechanism. METHODS A nude mouse model of human lung adenocarcinoma HCC827 cell subcutaneously implanted tumor was established and subsequently the nude mice were randomly divided into 6 erlotinib groups and a model group, with 10 nude mouse per group. Erlotinib groups were respectively gavaged with 5 mg.kg-1 erlotinib at 08:00, 12:00, 16:00, 20:00, 24:00 and morrow 04:00, while the model group was given the same volume fraction of captisol. The tumor volume and tumor mass were measured and the tumor growth inhibitory rate was calculated. The mRNA expression of epidermal growth factor receptor (EGFR), mitogen-acti-vated protein kinase (MAPK), cyclin-dependent kinase inhibitor 1A(P21Waf1) and the related protein level were detected by real-time quantitative PCR and Western blotting. RESULTS Compared with model group, the tumor volume and tumor mass of mice at the dosing time of 08:00 and morrow 04:00 were significantly decreased(P<0.05). Compared with dosing time at 20:00 group〔(0.70±0.36)g〕, the tumor mass of 08:00 group〔(0.30±0.17)g〕 and morrow 04:00〔(0.39±0.29)g〕 group was significantly decreased(P<0.05). The mRNA expression of EGFR and MAPK in the tumor group of 08:00 was lower than in group of 20:00(P<0.05), while the mRNA expression of P21Waf1 was significantly higher than that of model group( P <0.05). Compared with model group, the protein expression of p-EGFR and p-MAPK in tumor 08: 00 and morrow 04: 00 group was negative-regulated significantly (P<0.05). CONCLUSION The antitumor effect of erlotinib on the human lung adenocarcinoma implanted tumor nude mice model presents rhythmicity. The dosing time at 08:00 is the most effective. lts mechanism is likely related to EGFR/ MAPK/ P21Waf1 signal transduction pathway.