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Purpose: We intended to evaluate the superiority of cisplatin-based chronotherapy in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and investigate the relationship between the circadian rhythm and the variability of pharmacokinetics for cisplatin. Methods: Forty-one patients with advanced NSCLC were divided into two groups with minimization randomization, including routine group (24 cases) and chronotherapy group (17 cases). The clinical effect and toxicity between the two groups were investigated. The population pharmacokinetics of cisplatin was calculated using nonlinear mixed-effects modeling method. Results: There is no significant difference in total response rate between chronotherapy group (52.94 %) and routine chemotherapy group (50.00 %), p = 0.853. The rate of leucopenia (grade 3 or 4) in chronotherapy group (11.76 %) is significantly lower than that in routine chemotherapy (37.50 %), p < 0.05. The rate of neutropenia (grade 3 or 4) in chronotherapy group (11.76 %) is significantly lower than that in routine chemotherapy group (33.33 %), p < 0.05. The proportion of gastrointestinal toxicity (nausea, grade 1 vs 2) in chronotherapy group is significantly lower than that in routine chemotherapy, p < 0.05. When cisplatin was administered at 18:00, the CL was 1.38- and 1.22-fold higher than those administered at 6:00 for total and unbound cisplatin, respectively ( p < 0.05). Conclusions: Cisplatin-based chronotherapy has advantage in relieving side effects of chemotherapy, and circadian could influence the metabolism of cisplatin, and more clinical researches are needed. [ABSTRACT FROM AUTHOR]