The randomized phase III trial EGF100151 demonstrated that the combination of lapatinib plus capecitabine (L + C) significantly improved time to progression (TTP) compared with capecitabine alone (C) in heavily pretreated patients with HER2+ (ErbB2+) advanced or metastatic breast cancer. This analysis assessed the effects of study treatments on quality of life (QOL) among patients in EGF100151. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQoL (EQ-5D) questionnaires. Patients completed questionnaires during efficacy and safety assessment visits (i.e., at screening visit, every 6 weeks for the first 24 weeks, every 12 weeks thereafter, and at discontinuation of study treatment). Primary analyses compared the treatment groups based on change from baseline QOL. Exploratory analyses compared proportion of patients achieving minimum important differences (MID) in QOL scores and the relationship between QOL and tumor status. Quality of life for patients in both treatment groups was maintained during 24 weeks of follow-up. Adjusted mean changes from baseline in all QOL scores for the L + C arm were comparable to those for the C arm. The between-group differences ranged from 0.7 to 2.2 (FACT-B total) and 0.3 to 1.8 (EQ-5D visual analog scale) and were consistently in favor of the L + C arm, although not statistically significant. Patients with an objective tumor response or stable disease showed clinically meaningful differences in QOL scores compared to patients with progressive disease. A greater proportion of patients receiving L + C versus C achieved the MID for all five QOL scores, although differences were not statistically significant. The addition of lapatinib to capecitabine significantly increases TTP without any evidence of a deleterious effect on patients' QOL, confirming its clinical benefit in this heavily pretreated patient population with advanced HER2+ breast cancer that has progressed on trastuzumab therapy.