Background: Chemotherapy induced alopecia (CIA) is known to have a significant psychological and quality of life impact, mainly in women. While cold caps have been shown to decrease CIA, expense, availability, and extension of treatment durations are barriers for routine clinical use. Keratinocyte Growth Factor (KGF) has been shown to have cytoprotective effects on human keratinocytes in vitro and reduce apoptosis in human hair follicles. Based on this data, we hypothesized that KGF-Hair serum (KGF-HS) will prevent CIA in women undergoing chemotherapy as treatment for breast cancer. Methods: We designed a Simon 2-stage prospective study to test our hypothesis. Study was approved by our institutional review board and registered on clinicaltrials.gov (NCT04554732). In part 1 we planned to enroll 20 patients into a single arm. If ≥ 4 responses are noted, we proposed to initiate part 2: randomized double-blind placebo-controlled study. Patients with early-stage breast cancer (ESBC) who were scheduled to get at least 4 cycles of anthracycline or taxane based chemotherapy were included. Patients with inflammatory scalp conditions, hair loss disorder, scalp disorders were excluded. The primary endpoint was successful hair preservation using the Common Terminology Criteria for Adverse Events 4.0 scale at the end of 4 cycles of chemotherapy. Secondary end points included wig use and scores on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale. Results: Twenty patients completed part 1 of the study and were evaluable for primary endpoint. Mean age was 60 years and 70% were treated with taxane based chemotherapy. Successful hair preservation was noted in 0 of 20 women. Mean duration of treatment with KGF-HS was 4.6wks (range 2-10 weeks) before women came off study due to grade 2 hair loss. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to end of treatment. There were only 2 grade 1 events (1 rash and 1 itching) reported which resolved after coming off the KGF-HS. There were no serious adverse device events. Conclusions: Among women with early-stage breast cancer receiving chemotherapy with a taxane, anthracycline, or both, using KGF-HS did not prevent CIA. Further research is needed to investigated other novel topical options to prevent CIA. Clinical trial information: NCT04554732.