OBJECTIVES The impact of chemotherapy on patient reported outcomes (PRO) of patients with advanced non-small-cell lung cancer remains poorly understood. We performed a systematic review of the literature to address how first-line chemotherapy affects PRO. Our aims were: To evaluate patterns of reporting of PRO in randomized controlled trials of advanced non-small-cell lung cancer; To estimate the effects of first-line chemotherapy on PRO and the correlation between PRO and overall survival. METHODS We performed a Medline systematic review of published clinical trials from 1980 to 2008. Randomized, phase III trials of first-line chemotherapy against Best Supportive Care, placebo, or another chemotherapy regimen were eligible. We collected data on the type of PRO instrument, reported measures, effect-size, and whether there was a statistically significant result on any PRO favoring the experimental chemotherapy arm. We also computed overall survival differences between experimental and control arms and measured the correlation of OS difference with effect size for global QoL as assessed by the EORTC QLQ-C30 instrument. RESULTS Twenty-two trials from 1998 to 2008 reported PRO. U.S. contributed with only one trial (4.5%). In 6 trials, Best Supportive Care was the control arm (27%). The EORTC QLQ-C30/LC13 instrument was used in 14 (64%) trials. Effect-size was directly measured in only 2 trials, and calculated in 3 other trials. Mean effect size was 0.013 for chemotherapy vs. BSC (n=2) and 0.041 for chemotherapy vs. chemotherapy (n=2). Mean OS difference of chemotherapy vs. BSC was 1.9 months (P=0.04). Pearson correlation of OS difference and effect-size was –0.43. CONCLUSIONS Reporting of PRO in randomized controlled trials of advanced non-small-cell lung cancer remains highly variable. There remains a substantial uncertainty about the impact of chemotherapy on global QoL, but the net effect is likely small. A possible association of overall survival differences with global QoL awarrants further investigation.