The aim of the research was to examine the expression level of microRNA221/222 (miR-221/222) in the serum of patients with type 2 diabetes mellitus (T2DM) who are also diagnosed with post-menopausal breast cancer. We aimed to evaluate the differences in microRNA expression in patients with T2DM alone, patients with post-menopausal breast cancer alone, and patients with both T2DM and post-menopausal breast cancer. We selected 20 cases from a healthy control group, 30 cases from the group of patients with T2DM and obesity, 30 cases from the group of the patients with post-menopausal breast cancer, and 30 cases from the group of patients with both T2DM and post-menopausal breast cancer. The expression of miR-221/222 in the serum of the patients with post-menopausal breast cancer was higher than that of T2DM patients (P < 0.05), but lower than that of the T2DM patients who were also positive for post-menopausal breast cancer (P < 0.05); the expression of miR-221/222 in the serum of the T2DM patients was higher than that of the healthy controls (P < 0.05). BMI, HOMA-IR, HbA1c, and TG were positively correlated with the relative expression of miR-221/222 in the serum (P < 0.01). In conclusion, miR-221/222 participates in insulin resistance; the combination of miR- 221/222 and estrogen contributes to incidence of T2DM with post-menopausal breast cancer complications. MiR-221/222 may participate in the occurrence and progression of T2DM with post-menopausal breast cancer via down-regulation of CAVl.