Gefitinib is effective as first-line therapy for advanced nonsmall cell lung cancer (NSCLC). However, after failure of gefitinib, it is unknown whether any second-line regimens could lead to better outcomes. To study the influence of different second-line antitumor regimens on the outcomes of patients with NSCLC after failure of first-line gefitinib, we carried out a retrospective study in a tertiary referral medical center to investigate the prognosis of patients with NSCLC receiving second-line antitumor treatment after gefitinib therapy. Clinical data and epidermal growth factor receptor (EGFR) mutational status of tumors were collected. A total of 195 patients with Stage IIIb or IV NSCLC receiving first-line gefitinib and at least 1 subsequent line therapy were identified. A second-line therapy with a platinum-based combination or taxane-containing regimen were associated with a higher therapy response, whereas a platinum-based combination was linked to better overall survival. Ninety-five patients had tumors with known EGFR mutation status; 61 had EGFR mutations and 34 had wild-type EGFR. A second-line therapy with a gemcitabine/platinum combination regimen resulted in better overall survival than erlotinib in patients with EGFR mutations (p = 0.035) but not in patients with wild-type EGFR (p = 0.785). The study suggested that, after failure of first-line gefitinib therapy, second-line platinum-based combination regimens were associated with a better overall survival than other regimens, including erlotinib. The survival benefit of platinum-based combination regimens existed in patients with mutant EGFR but not wild-type EGFR.