The objective of this study is to identify whether decline in cognitive functioning after chemotherapy in women with breast cancer is associated with health/disease, treatment, and psychological variables. Neuropsychological performance, health/disease, and treatment-related information of 136 women with breast cancer (age M  = 49.38;  SD  = 7.92; range = 25.25–67.92) was assessed pre-chemotherapy and 1-month post-chemotherapy. The Reliable Change Index corrected for practice (RCIp) identified women whose performance significantly declined, while Pearson correlations assessed the relationship between cognitive change and predictor variables. A total of 16.9% of women showed signifi cant decline post-chemotherapy, with affected domains including verbal learning and memory, abstract reasoning, and motor coordination. Decline in hemoglobin levels and increased anxiety over the course of chemotherapy was found to significantly predict impairment in multiple cognitive measures. Change in specific cognitive measures was significantly associated with baseline fatigue, depression, and functional well-being ( r  = 0.23 to 0.33;  p  = .01 to < .001). Although the effects are small, there is evidence that psychological and health factors may increase vulnerability to cognitive dysfunction after chemotherapy for breast cancer. Significant associations reported in this study may be useful in the identification and treatment of at-risk individuals.