Background: Cog complaints are common among women receiving adjuvant therapy (Rx) for ESBC. Longitudinal prospective data is needed to help identify predictors of cog decline. We conducted a prospective trial to evaluate the effects of chemo- (CTX) & hormone therapy (HRx) on brain & cog fcn in pts with ESBC using multiple objective & subjective tests as well as MRI/PET imaging. Here we report evaluation of clinical characteristics that predict decline in cog fcn. Methods: Eligibility included female patients (pts) planning to receive adjuvant Rx for ESBC. Pts were enrolled in 3 Rx groups (grps): CTX, CTX & HRx, and HRx, with a 4^thno Rx age/education matched control grp. All pts underwent a battery of objective & subjective cog tests before start of Rx, 1 mo after CTX or 5 mo after start of HRx (FU1), then 9 mo (FU2) & 18 mo (FU3) after CTX. Brain MRI, PET & serum estradiol (E) were performed at baseline, FU1 & FU2. Results: 81 pts were enrolled as follows, 14 CTX, 33 CTX & HRx, 22 HRx, 12 control. 90% completed FU1, 72% FU2, & 62% FU3, with 29 pts waiting to complete testing. Demographics were similar between grps, median age 54, 78% Caucasian. At each FU, ~25% of pts showed decline in cog fcn compared to the prior time point using a reliable change index; 51% showed decline at > 1 time point, primarily in tests measuring executive function & verbal memory. 62% of pts who declined from baseline to FU1 later stabilized or improved; 77% of pts who declined from FU1 to FU2 later stabilized or improved. Compared to controls, receipt of CTX & HRx (OR 3.15, p=.008), or HRx overall (OR 4.94, p=.004) but not serum E, menopausal status, or CTX, were significant predictors of decline at any time point. Rx group did not predict poorer perceived cog fcn (FACT-COG); depression & fatigue did not predict decline in objective cog fcn. Conclusions: Decline in cog fcn is common in pts receiving adjuvant Rx for ESBC. Predictors included CTX & HRx, or HRx overall but not other treatment & pt related factors. Ongoing HRx, particularly after CTX, appears to be a risk factor for worse cog fcn. Pts should be aware that HRx may be a risk factor for cog deficits, & intervention studies should be designed to focus on this group of pts. Funding: NIH R01 1AG025303-01A2. Clinical trial information: NCT00755313.