Purpose: To investigate whether 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) may be a potential tool to select a subgroup of patients who might be spared maintenance treatment, if the metabolic response after first-line chemotherapy could predict time-to-progression (TTP). Experimental Design: A total of 43 patients who underwent baseline FDG-PET scan and did not show disease progression (DP) after 4 cycles of first-line chemotherapy were enrolled and underwent second FDG-PET 3 weeks after completion of the first-line chemotherapy. The primary endpoint was to compare percent decrease in maximum standard uptake value (SUVmax) between early (TTP after second PET examination <8 weeks) and late (TTP ≥8 weeks) DP subgroups. Secondary endpoints were to determine whether fractional decrease in SUVmax could predict TTP and overall survival (OS), both calculated from the date of the second FDG-PET. Results: Percent decreases in SUVmax in late DP subgroup were greater than those in early DP subgroup (mean reduction, 54.7% ± 27.2% vs. 27.8% ± 46.8%, P = 0.021). Receiver operating characteristic curves identified a 50.0% decrease in SUVmax as the optimal threshold to distinguish these subgroups. Using this value as the cutoff resulted in a positive predictive value of 82.6% and negative predictive value of 60.0% in predicting TTP ≥8 weeks. Patients with SUVmax decrease <50% had significantly longer median TTP (3.0 vs. 1.5 months, P = 0.001) and OS (not reached vs. 14.2 months, P = 0.003). Conclusions: Fractiohal decrease in SUVmax of the main lesion after completion of 4 cycles of chemotherapy may discriminate patients with TTP ≥8 weeks and predict TTP and OS in patients with advanced NSCLC.