OBJECTIVES: Treatment of advanced non-small cell lung cancer (NSCLC) involves balancing the efficacy and tolerability of treatments, including the impact of disease progression on health-related quality of life (HRQOL).  We report findings from a prospective medical record registry that examined HRQOL as measured by patient reported outcomes (PROs) in patients (pts) newly diagnosed with advanced NSCLC through one year of follow-up. METHODS: Pts starting first-line treatment of stage IIIB/IV nonsquamous NSCLC were prospectively enrolled and consented at 34 US-based community oncology settings.  PROs were collected once per cycle during treatment, and at each visit if patients discontinued treatment.  PROs included the EORTC QLQ-C30 and QLQ-LC13, the MDASI-LC, and the Rotterdam Activity Level Scale (RALS).    RESULTS: Of 155 eligible pts enrolled, 145 provided follow-up data, including 1,100 PRO surveys.  Pts received standard, widely used chemotherapy regimens, and were 58.5% male, 86.4% Caucasian, with mean age 64.8 (±10.9) years.  13.6% had impaired performance status (ECOG 2+ or equivalent).  PFS events occurred in 141 of 147 pts (95.9%) based on scan records and physician progress notes, with overall median PFS of 5.59 (4.83-6.25) months.  Fifty-nine pts provided PRO data after disease progression.  Linear mixed models showed that disease progression was associated with significant or near significant adverse impact on HRQOL in 18 of 32 PRO endpoints.  Among the 12 significant effects, the average adverse effect of disease progression was 5.7% of the instrument range, where 5% - 10% change is the minimum important difference (Ringash, et al., 2007).  The strongest effects were QLQ-LC13, Sore mouth (8.0%) and Dyspnea (7.3%), and QLQ-C30 constipation (7.6%).  Effects on the QLQ-C30 Global Health Status and Physical Functioning measures were 4.7% and 5.3%, respectively (all p < 0.05).  CONCLUSIONS: PROs showed significant and clinically meaningful worsening of symptoms at disease progression, as indicated by widely used HRQOL measures.