BACKGROUND: The CALM-PD trial evaluated the development of motor complications in subjects with early Parkinson disease (PD) randomized to initial treatment with either pramipexole or levodopa. A secondary finding of the trial was a higher than anticipated development or worsening of somnolence and edema and development of hallucinations. OBJECTIVES: To investigate risk factors for somnolence, edema, and hallucinations in patients with early PD initiating dopaminergic therapy. METHODS: This was a secondary analysis of data from the CALM-PD trial. Baseline patient characteristics were evaluated for their associations with the development or worsening of somnolence and edema and the development of hallucinations using Cox proportional hazards regression models. RESULTS: Kaplan-Meier estimates of the 4-year incidence of the development or worsening of somnolence and edema and the development of hallucinations were 35%, 45%, and 17%. Initial pramipexole treatment (hazard ratio [HR] 2.22, 95% CI 1.41, 3.50, p < 0.001), male gender (HR 1.79, 95% CI 1.09, 2.93, p = 0.02), and >5 systems with a comorbid illness (HR 1.62, 95% CI 1.04, 2.51, p = 0.03) were associated with somnolence. Initial pramipexole treatment (HR 3.18, 95% CI 1.95, 5.18, p < 0.0001), female gender (HR 1.46, 95% CI 0.94, 2.27, p = 0.09), and comorbid cardiac disease (HR 1.59, 95% CI 1.02, 2.47, p = 0.04) were associated with edema. Age > or =65 (HR 2.06, 95% CI 0.98, 4.32, p = 0.06), Mini-Mental State Examination score >28 (HR 0.42, 95% CI 0.19, 0.91, p = 0.03), and >5 systems with a comorbid illness (HR 3.42, 95% CI 1.59, 7.38, p = 0.002) were associated with hallucinations. CONCLUSIONS: Comorbid illnesses are important and overlooked risk factors for the development of somnolence, edema, and hallucinations. When initiating therapy with pramipexole, patients should be counseled about and monitored for somnolence and edema. Slight decrements in cognitive function and older age are associated with an increased risk of hallucinations.