Study Objective Dehydroepiandrosterone ( DHEA ) and its sulfated form ( DHEAS )—jointly referred to as DHEA (S)—are neurosteroids known to regulate brain development and function that have been found to be positively correlated with cognitive function. It is unknown whether prechemotherapy plasma DHEA (S) levels are associated with the onset of cancer‐related cognitive impairment ( CRCI ). The objective of this study was to evaluate whether an association exists between prechemotherapy plasma DHEA (S) levels and onset of CRCI in patients with breast cancer receiving chemotherapy. Design Multicenter, prospective cohort study. Setting Two specialized cancer centers in Singapore. Patients Eighty‐one patients with early‐stage breast cancer (stages I– III ) who had no prior exposure to chemotherapy and/or radiotherapy and were scheduled to receive anthracycline‐based or taxane‐based chemotherapy treatment with curative intent. Measurements and Main Results Patients completed assessments for self‐perceived and objective cognitive function at three time points: prechemotherapy (T1), during chemotherapy (T2), and after chemotherapy (T3). Plasma samples were collected prior to chemotherapy, and DHEA (S) levels were quantified by using ultra–high‐performance liquid chromatography–tandem mass spectrometry. Multivariable logistic regression was used to adjust for clinically important factors and to evaluate the association between prechemotherapy plasma DHEA (S) levels and CRCI . Mean ± SD age was 48.9 ± 9.3 years, with 27.8% of patients experiencing clinically significant cognitive impairment based on global Functional Assessment of Cancer Therapy–Cognitive Function scores. The mean ± SD prechemotherapy plasma DHEAS and DHEA levels were 1.61 ± 0.91 μmol/L and 19.21 ± 13.13 nmol/L, respectively. Prechemotherapy DHEAS levels were found to be associated with impairment in the self‐perceived cognitive domains of verbal fluency (adjusted odds ratio [ OR ] 0.27, 95% confidence interval [ CI ] 0.08–0.96) and mental acuity (adjusted OR 0.25, 95% CI 0.08–0.74). Conversely, DHEA levels were not associated with impairment in any cognitive subdomains. Conclusion Our findings suggest that patients with higher prechemotherapy DHEAS levels had lower odds of developing self‐perceived cognitive impai...