Purpose: The incidence of ductal carcinoma-in-situ (DCIS) of the breast has been increasing. However, uncertainties exist about its prognosis, optimal treatment, and effect on women's health-related quality-of-life (HRQoL). Our study assessed the prospective changes in HRQoL in women diagnosed with DCIS. Patients and Methods: Between 1992 and 2000, HRQoL was assessed at three 4-year intervals among women enrolled in two Nurses' Health Study cohorts using the Medical Outcomes Survey Short-Form 36 health survey. Using mixed effects and logistic regression modeling, we compared the prospective changes in HRQoL scores among women with and without DCIS. Results: The study included 114,728 women; 510 were diagnosed with DCIS during the study period. During 4 years, women with DCIS had small, but statistically significantly greater declines in the domains of role limitations due to physical problems (-6.74; SE, 1.69), vitality (-2.06; SE, 0.78), and social functioning (-2.40; SE, 0.93) than women without DCIS. Among those with DCIS, clinically significant declines were more often observed within 6 months of the diagnosis in the domains of social functioning (odds ratio, 1.78; 95% CI, 1.03 to 3.07) and mental health (odds ratio, 2.03; 95% CI, 1.09 to 3.79) than after 6 months after diagnosis. Conclusion: Women with DCIS experienced small long-term declines in HRQoL, although these declines did not seem to be clinically important. Short-term clinically significant declines in the psychosocial domains were noted. In counseling women with DCIS, clinicians should provide reassurance but prepare them to deal with the short-term sequelae.