Purpose To compare docetaxel-based doublet with single-agent docetaxel as second-line treatment in non-small-cell lung cancer (NSCLC). Methods We systematically searched for randomized clinical trials that compared docetaxel-based doublet with single-agent docetaxel in patients with histologically proven non-small-cell lung cancer. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, 1-year survival rate, and grade 3 or 4 toxicity. Data were extracted from the studies by two independent reviewers. The meta-analysis was performed by Stata version 10.0 software (Stata Corporation, College Station, TX, USA). Results Eight randomized clinical trials (totally 2,126 patients) were eligible. Meta-analysis showed that there was significant improvement in PFS (HR 0.81, 95% CI 0.69-0.96, P = 0.013) and overall response rate (OR 1.42, 95% CI 1.13-1.80, P = 0.03) in docetaxel-based doublet group, compared with docetaxel alone, though the pooled HR for overall survival (HR 0.93, 95% CI 0.80-1.07, P = 0.308) showed no significant difference between the two groups. However, there were more incidences of grade 3 or 4 neutropenia (OR 1.2, 95% CI 1.00-1.45, P = 0.05), thrombocytopenia (OR 4.53, 95% CI 1.75-11.75, P = 0.002), and diarrhea (OR 1.78, 95% CI 1.16-2.74, P = 0.008) in docetaxel-based doublet group. With regard to the risk of grade 3 or 4 anemia (OR 1.95, 95% CI 0.62-6.17, P = 0.25), fatigue (OR 1.09, 95% CI 0.75-1.59, P = 0.66), and nausea and vomiting (OR 1.75, 95% CI 0.78-3.91, P = 0.17), there was no significant difference between the two groups. Conclusions This was the first meta-analysis of docetaxel-based doublet versus single-agent docetaxel as second-line therapy in the treatment of non-small-cell lung cancer. The results indicated that docetaxel-based doublet therapy did not gain any benefit in survival but significantly improved PFS and better ORR versus single-agent docetaxel. However, more incidences of grade 3 or 4 neutropenia, thrombocytopenia, and diarrhea were observed in docetaxel-based doublet group.