Greater chronic disease burden may decrease quality of life (QOL) of breast cancer survivors. Our objective was to investigate the association between chronic disease burden and QOL in breast cancer survivors at 1 year post-diagnosis. We analyzed cross-sectional data collected 1 year post-diagnosis from a sample of female breast cancer survivors identified from the Missouri cancer registry. We used eight RAND-36 subscales to assess physical, emotional, and social functioning QOL domains. Using Katz's measure of comorbidity, we computed chronic disease burden (0, 1, and 2+). Multivariable general linear models for each QOL subscale were used to examine associations between chronic disease burden and QOL after controlling for potential covariates: socio-demographic, clinical, psychosocial, behavioral risk factors, and access to medical care. Participants (n = 1089) were 58-year old on average (range 27-96) and mostly White (92%), married (68%), had at least a high school education (95%), and had health insurance (97%). Sixty-six percent of survivors had a chronic disease burden score of 0, 17% had 1, and 17% had 2+. Chronic disease burden was significantly associated with each QOL subscale in crude models (P < 0.001). In fully adjusted models, chronic disease burden was still significantly correlated with six subscales, but not with the emotional well-being and role limitations due to emotional problems subscales. One year post-diagnosis, breast cancer survivors with higher chronic disease burden had lower physical and social functioning than survivors without additional health conditions. These differences were not fully explained by relevant covariates. Identifying modifiable targets for intervention will be critical for improving QOL outcomes among survivors who have other chronic health conditions.