Background: Breastfeeding durations in the United States fall short of public health objectives. We sought to quantify the prevalence and identify risk factors for early, undesired weaning that mothers attribute to physiologic difficulties with breastfeeding. Methods: We analyzed data from the Infant Feeding Practices Study (IFPS) II, a longitudinal study of US women. We defined disrupted lactation as early, undesired weaning attributed to at least two of the following three problems: breast pain, low milk supply, and difficulty with infant latch. We used logistic regression to estimate the association maternal body mass index (BMI), postpartum depressive symptoms, and disrupted lactation. Results: Of 4,902 women enrolled in the IFPS II, we analyzed 2,335 women who reported prenatal intention and breastfeeding initiation. The prevalence of disrupted lactation was 12 per 100 women (95% confidence interval [CI] 11, 13) during the first year of life. Women in this group weaned earlier (median 1.2 months, interquartile range [IQR] 0.5-2.8) than women without disrupted lactation (median 7.0 months, IQR 2.8-2.0, p < 0.01). In multivariable-adjusted (MV-adj.) models, we found increased odds of disrupted lactation among overweight (odds ratio [OR] 1.6, 95% CI 1.1-2.3) or obese (OR 1.7, 95% CI 1.2-2.6) women, compared with women with a normal pregravid BMI. Maternal depressive symptoms at 2 months, defined as Edinburgh Postnatal Depression Scale ‡ 13, were also associated with disrupted lactation (MV-adj. OR 1.7, 95% CI 1.1-2.7). Conclusion: In a longitudinal sample of US women, disrupted lactation affected one in eight mothers who initiated breastfeeding. These findings underscore the need for both improved early breastfeeding support and targeted research to define the underlying pathophysiology and to determine management strategies that will enable more mothers to achieve their breastfeeding goals.