Improvement of health‐related quality of life (HRQoL) is one of the primary objectives of symptomatic therapies in Parkinson's disease (PD). The aim of this observational study was to investigate possible changes in generic HRQoL in relation to changed PD pharmacotherapy in the clinical setting.A total of 219 outpatients with mild to moderate PD (median H&Y score = 2.0), treated with oral antiparkinsonian medications, were investigated twice with a 6‐month interval. At baseline, PD medication dose was increased for 82 patients for clinical reasons (median increase of 100 mg levodopa equivalent daily dose or 31.9%), whereas medication remained unchanged for 137 patients. Two generic HRQoL questionnaires, EQ‐5D and 15D, were used at baseline and at 6 months, and the baseline and delta HRQoL values were compared between the treatment groups.In the entire sample, the EQ‐VAS score decreased during the study period, indicating a general decline in HRQoL (P = 0.04). There were no differences in the baseline HRQoL values or delta values between the treatment groups as measured with EQ‐5D or 15D (levodopa dose elevated vs dopamine agonist/MAO‐B inhibitor dose elevated vs no change in medication).An approximately 1/3 increase in antiparkinsonian medication dose did not have an impact on generic HRQoL. Disease‐specific QoL may be more sensitive to pharmacotherapy‐related changes in PD.