Objective Although health-related quality of life (HRQOL) has been included in multiple Parkinson's disease (PD) clinical trials, little is known about how HRQOL responds to treatments over time. Here we assess the effect of therapy on HRQOL and explore factors that influence the HRQOL profiles and subdomains. Method A total of 301 subjects with early PD were randomized to either initial pramipexole or initial levodopa and followed every 3 months over a 4-year period. To estimate health outcomes, we used EQ-5D and PDQUALIF. We calculated the incremental effectiveness as the accumulated difference in the total HRQOL over time between treatments. The subgroup analyses (by sex, race, age, baseline patient characteristics, and occurrence of adverse events) were conducted using the same approach. Sensitivity analysis was performed to test the effect of missing data imputation on the results. Results All three HRQOL measures resulted in similar profiles over time characterized by initial improvement over the first 3 to 6 months and followed by a gradual decline in years 2, 3, and 4. The difference in HRQOL between the treatment arms widened in favor of pramipexole in years 3 and 4 for all HRQOL measures used (EQ-5D: Y3 0.048, P = 0.03; Y4 0.071, P = 0.04). Our analyses suggested that the effect of pramipexole on HRQOL was mediated through nonmotor functions, whereas levodopa improved primarily motor domains of HRQOL. Conclusion Our results suggest that pramipexole and levodopa affect patient HRQOL via improvement on different domains of well-being: nonmotor effect for pramipexole and mobility improvement for levodopa.