Studies systematically comparing the performance of health-related quality-of-life (HRQoL) instruments in pulmonary arterial hypertension (PAH) are lacking. We sought to address this by comparing cardiac and respiratory-specific measures of HRQoL in PAH. We prospectively assessed HRQoL in 128 patients with catheterisation-confirmed PAH at baseline and at 6, 12 and post-24 month follow-up visits. Cardiac-specific HRQoL was assessed using the Minnesota Living with Heart Failure Questionnaire (LHFQ); respiratory-specific HRQoL was assessed using the Airways Questionnaire 20 (AQ20); and general health status was assessed using the 36-item Short Form physical component summary (SF-36 PCS). The LHFQ and AQ20 were highly intercorrelated. Both demonstrated strong internal consistency and converged with the SF-36 PCS. Both discriminated patients based on World Health Organization (WHO) functional class, 6-min walking distance (6MWD) and Borg dyspnoea index (BDI), with the exception of a potential floor effect associated with low 6MWD. The LHFQ was more responsive than the AQ20 to changes over time in WHO functional class, 6MWD and BDI. In multivariate analyses, the LHFQ and AQ20 were each longitudinal predictors of general health status, independent of functional class, 6MWD and BDI. In conclusion, both cardiac-specific and respiratory-specific measures appropriately assess HRQoL in most patients with PAH. Overall, the LHFQ demonstrates stronger performance characteristics than the AQ20.