Background:Fatigue is the most common and disturbing complaint reported by women during adjuvant breast cancer chemotherapy, but little is known about the mechanisms influencing it.Objectives:To test an explanatory model of variables influencing fatigue in women during the first three cycles of adjuvant breast cancer chemotherapy and to determine the extent to which model variables explain fatigue at treatments and predict fatigue at cycle midpoints.Methods:A prospective, correlational design with repeated measures was used. The sample included 60 women who received chemotherapy after surgery for Stage I or II breast cancer. Fatigue was measured by the Piper Fatigue Scale. Predictor variables and measures were health and functional status (MOS SF-36), chemotherapy protocol, health-promoting lifestyle behaviors (HPLPII), nutritional status (hematocrit [Hct] and body mass index [BMI]), symptom distress (MSDS), and initial reaction to the diagnosis of cancer (RDCQ). Multiple regression was used for path analyses.Results:Trimmed models of influences on fatigue were identified. At treatments, direct influences on fatigue were symptom distress (β = 0.45-0.76,p= 0.002-0.001), chemotherapy protocol (β = 0.26,p= 0.02), and interpersonal relations (IPR) behaviors (β = −0.28,p= 0.02); indirect influences were confronting reaction to the diagnosis through IPR behaviors and through symptom distress. At cycle midpoints, direct influences on fatigue were symptom distress from the previous treatment (β = 0.36-0.43,p= 0.004-0.001), physical and social function (β = −0.31-0.50,p= 0.02-0.001), and IPR behaviors (β = −22,p= 0.05); an indirect influence was confronting reaction to the diagnosis (through IPR behaviors). Variance explained in fatigue ranged from 42% to 62% at treatments and from 40% to 56% at cycle midpoints.Conclusions:Further testing of the model is warranted. Findings suggest that interventions to reduce symptom distress and promote health and functional status need to be developed and evaluated for effectiveness in modifying fatigue during adjuvant breast cancer chemotherapy.