Hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are the common diagnostic/prognostic markers in breast cancer. Few articles have recently reported the correlation between cytology and molecular subtypes. We combined nuclear morphological characteristics with HR and HER2 status to observe the relationship and provide ideas for machine learning.We reanalyzed fine-needle aspiration cytology samples and core-needle puncture histological specimens from 142 patients with invasive breast cancer between March 2019 and December 2019, and the findings were compared with the two groups (HR+/HER2- and HR-/HER2+) following nuclear cytomorphological features: nuclear/cytoplasmic ratio, difference of nuclear size, nuclear pleomorphism, chromatin feature, nuclear membrane and nucleoli, and Nottingham grading.Two groups were significantly associated with the difference of nuclear size, nuclear pleomorphism, and nucleoli (P < 0.001) and consistent with histological grading (P < 0.001). Moreover, nucleolar characteristics of size and number had obviously statistical significance (P < 0.001). Multiple micro-nucleoli were frequently seen in the HR+/HER2- group compared with the HR-/HER2+ group which mostly were observed centered medium-large nucleoli. We described four interesting nuclear morphologies in the experiment.There were significant differences in nuclear characteristics between two groups. HR and HER2 status not only might be predicted in cytological samples, but some specific nuclear morphological features might have potential value to help us understand molecular function and predict more information.Copyright © 2021 Jiayu Li et al.