Lyme borreliosis (LB) can manifest as a localized infection or, if left untreated, disseminated disease. This analysis used Patient-Reported Outcome tools to assess general health, fatigue, pain, and cognitive function in patients with localized or disseminated LB, compared with age- and site-matched controls without LB. All participants were enrolled in the Burden of Lyme Disease (BOLD) study; LB cases were assessed at 3 time points: the enrollment visit, and two follow-up visits conducted within 10 months of enrollment. Controls were evaluated at 2 time points: the enrollment contact and a follow-up contact 16-18 months post-enrollment. Symptom severity and general health quality between groups were compared using two-tailed Student's t-tests and multivariate regression analyses. Disseminated LB cases reported greater fatigue and pain than localized LB (disseminated LB fatigue scores: 4.1, 3.7, and 3.5 at Visits 1, 2, and 3, respectively vs. localized LB: 2.9, 3.0, and 2.9; disseminated LB pain scores: 2.5, 1.6, and 1.3 vs. localized LB: 0.9, 0.6, and 0.8) and controls (fatigue score: 3.2; pain score: 1.0). Disseminated LB was also associated with reduced health-related quality of life. The results of this study indicate that health-related quality of life may vary by disease stage and that patients with disseminated disease showed persistent impairment during the acute phase and at 10-month follow-up.