The aim of this prospective study was to evaluate the value of 18F-FDG PET for the assessment of chemotherapy response in patients with non–small cell lung cancer. Furthermore, part of the objective of this study was to compare 2 methods to quantify changes in glucose metabolism. Methods: In 51 patients, dynamic 18F-FDG PET was performed before and at 5–8 wk into treatment. Simplified methods to measure glucose metabolism (standardized uptake value [SUV]) and quantitative measures (metabolic rate of glucose [MRGlu]), derived from Patlak analysis, were evaluated. The overall survival and progression-free survival with respect to MRGlu and SUV were calculated using Kaplan–Meier estimates. Fractional changes in tumor glucose use were stratified by the median value and also the predefined EORTC (European Organization for Research and Treatment of Cancer) metabolic response criteria, and criteria applying cutoff levels similar to those of RECIST (Response Evaluation Criteria in Solid Tumors) were evaluated. Results: When stratifying at the median value of ΔMRGlu and ΔSUV, the difference in overall survival (P = 0.017 for ΔMRGlu, P = 0.018 for ΔSUV) and progression-free survival (P = 0.002 for ΔMRGlu, P = 0.0009 for ΔSUV) was highly significant. When applying the predefined criteria for metabolic response, the cutoff levels as also used for size measurement (RECIST) showed significant differences for ΔSUV between response categories in progression-free survival (P = 0.0003) as well as overall survival (P = 0.027). Conclusion: The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by 18F-FDG PET is highly predictive for patient outcome, stratifying patients into groups with widely differing overall survival and progression-free survival probabilities. The use of 18F-FDG PET for therapy monitoring seems clinically feasible, because simplified methods to measure tumor glucose use (SUV) are sufficiently reliable and can replace more complex, quantitative measures (MRGlu) in this patient population.