BACKGROUND: Midterm change in health-related quality of life (HRQOL) by left ventricular assist device (LVAD) implant strategy is unknown. The purpose of this study was to examine HRQOL by pre-operative implant strategy from before to 2 years after surgery. METHODS: Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support were stratified into 3 groups based on pre-implant device strategy: destination therapy (DT) (n = 2,901), bridge to transplant (BTT) (n = 2,209), and bridge to candidacy (BTC) (n = 3,076). HRQOL data were collected before and 2 years after surgery using the generic EQ-5D-3L survey and heart failure–specific Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Statistical analyses included chi-square tests, analysis of variance, paired t-tests, and general linear random effects models. RESULTS: Between April 1, 2008 and June 30, 2013, 4,422 patients and 1,660 patients (majority males and ≥50 years) who received primary continuous flow LVADs completed baseline EQ-5D-3L and KCCQ-12 questionnaires, respectively, whereas 1,615 and 1,408 patients completed EQ-5D-3L and KCCQ-12 questionnaires at 2 years, respectively. Although paired t-tests and general linear random effects models showed that both heart failure–specific and generic HRQOL improved for all groups across time (p-values <0.05), some differences in HRQOL were found by implant strategy at baseline and 2 years, with a pattern favoring better functioning for patients with BTT. The BTT group reported significantly higher overall HRQOL pre-implant using the KCCQ-12 (BTT = 37.09, BTC = 33.57, and DT = 33.56) and at 2 years using the EQ-5D-3L (BTT = 75.18, BTC = 72.27, and DT = 70.87) (p-values <0.05), although these differences were not clinically important differences. Differences in HRQOL domains were also found. CONCLUSIONS: Using generic and heart failure–specific instruments, overall HRQOL generally improved from before to 2 years after mechanical circulatory support implant regardless of implant strategy, although important domain-specific differences by group were identified.