Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are used as the standard first-line treatment for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, the impact of comorbidities and treatment toxicities on quality of life (QoL) was seldom investigated. We aimed to investigate the association of comorbidities, adverse events (AEs), and QoL in treatment-naïve advanced NSCLC patients receiving EGFR-TKI treatments. This multi-center prospective observational study was conducted to evaluate QoL and AEs at baseline, the 2nd, 4th, 12th, and 24th week. Clinical characteristics, comorbidities, and pre-treatment laboratory data were recorded. QoL was assessed by using the summary score of the EORTC QLQ-C30 and the dermatology life quality index. The impact of comorbidities, neutrophil-to-lymphocyte ratio (NLR), and AEs on QoL was analyzed by generalized estimating equations. A total of 121 patients were enrolled. Diarrhea (p=0.033), anorexia (p<0.001), and NLR ≥4 (p=0.017) were significantly associated with a QoL impairment. Among skin toxicities, acneiform rash (p=0.002), pruritus (p=0.002), visual analogue scale for pruritus (≥3 and<7, p=0.006; ≥7, p=0.001) and pain (1-3, p=0.041) were associated with a QoL impairment. No significant association was found between comorbidities and QoL changes. Diarrhea, anorexia, skin pain, and pruritus may cause a deterioration in QoL in patients receiving EGFR-TKI therapy. NLR may be a potential predictive factor for QoL impairment. Aggressive management and close monitoring for these clinical factors are crucial to improve QoL.