Objective: To explore the effect of virtual touch tissue imaging quantification (VTIQ) combined with serum carcinoma marker 153 (Ca153) on the evaluation of benign and malignant breast nodules. Methods: A total of 112 patients with breast parenchymal nodules who were treated in Jianhu County People’s Hospital from January 2020 to December 2021 were retrospectively selected as research subjects. Using postoperative pathological results as the gold standard, 112 patients with breast nodules were divided into a malignant and a benign group. The sensitivity, predictive value, accuracy rate, missed diagnosis rate, misdiagnosis rate of nodule shear wave velocity (SWV), serum Ca153, and their combination in diagnosing benign and malignant breast nodules. The consistency of the diagnosis of benign and malignant breast nodules and the pathological results were compared among the 3 methods. Results: Pathological examination of 112 breast nodules showed that there were 79 benign breast nodules and 33 malignant breast nodules. The SWV value and Ca153 in the malignant breast nodule group were significantly higher than those in the benign breast nodule group, and the difference was statistically significant (P<0.05). The ROC curve shows that the optimal thresholds of SWV value and Ca153 level for the diagnosis of benign and malignant breast nodules were 4.385 m/s and 31.465 U/mL. The SWV value of VTIQ technique had a sensitivity of 78.79% (26/33) in diagnosing malignant breast nodules; the sensitivity of diagnosing benign breast nodules was 96.20% (76/79); the sensitivity of serum Ca153 in diagnosing breast nodule malignancy was 72.73% (24/33); the sensitivity of diagnosing benign breast nodules was 98.73% (78/79); the sensitivity of combined diagnosis of breast nodule malignancy was 93.94% (31/33); the sensitivity for diagnosing benign breast nodules was 100.00% (79/79). Compared with the pathological examination, the SWV value of VTIQ technology in the diagnosis of benign and malignant breast nodules had a Kappa value of 0.837, and the two were in good agreement. Compared with the pathological examination, the Kappa value of serum Ca153 in the diagnosis of benign and malignant breast nodules was 0.769, and the two were in good agreement. Compared with the pathological examination, the Kappa value of the joint diagnosis of benign and malignant breast nodules was 0.956, and the consistency between the two was good. The Kappa value of the combined diagnosis was significantly higher than the SWV value of VTIQ technology and serum Ca153 alone diagnosis Kappa value (P<0.05). There was no significant difference in missed detection rate and misdiagnosis rate among VTIQ technology, serum Ca153, and their combined diagnosis (P>0.05). However, the accuracy of the 2 combined diagnosis of benign and malignant breast nodules was higher than that of VTIQ technology and serum Ca153 (P<0.05). Conclusion: Virtual touch tissue imaging quantification technology combined with serum Ca153 has high value in the diagnosis and differentiation of benign and malignant breast nodules and can effectively improve the diagnostic accuracy.