The purpose of this analysis was to assess the impact of pretreatment factors on quality of life (QOL) in patients with locally advanced nonsmall cell lung cancer (NSCLC). In particular, this study focused on the possible interaction between gender-specific baseline health-related QOL and Karnofsky performance score (KPS) in a prospective randomized lung cancer trial. QOL information, using validated instruments (Functional Assessment of Cancer Therapy-Lung [FACT-L], version 2, and Functional Living Index-Cancer [FLIC]), was prospectively collected in patients with locally advanced NSCLC treated on Radiation Therapy Oncology Group (RTOG) trial 89-01. Between April 1990 and April 1994, 70 eligible patients participated in a phase III trial comparing a regimen containing sequential chemotherapy and radiation therapy versus sequential chemotherapy plus surgery. Of these 70 patients, 46 underwent pretreatment FLIC and 49 underwent pretreatment FACT-L. There was a significant interaction between gender and KPS using FLIC (P = 0.009), which also showed a trend toward significance with FACT (P = 0.09). Significant KPS-by-gender interactions were noted for FACT-L in the physical well-being and additional concerns-lung subscales (P = 0.012 and P = 0.0003, respectively). The results of both the FLIC and FACT-L demonstrated significantly lower scores corresponding to lower KPS values (P = 0.009 and P = 0.016, respectively). Results of this randomized study incorporating prospective QOL measurements suggested that in patients with locally advanced NSCLC, analyzing QOL data by either gender or performance status alone may not accurately reflect how these factors depend upon each another. Understanding the interaction between gender and performance status could lead to better prognosticators and potentially could tailor interventions for specific groups of patients with lung cancer.