Abstract Background The combined immunohistochemical (IHC) analysis of the oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and proliferation index (Ki67) allows the approximation of the molecularly-defined breast cancer subtypes. As this classification is now increasingly being used to determine the adjuvant therapy choice in early breast cancer patients, the additional role of traditional prognostic factors in each distinct tumour subtype deserves further investigation. Methods A total of 1,202 women undergoing surgery for Early Breast Cancer (EBC) were selected for this retrospective analysis. Breast cancer subtypes were defined as luminal A, luminal B, HER2 luminal, HER2 enriched and Triple Negative [TN] by combining IHC. Kaplan-Meier survival analysis and log rank tests were used to determine Event Free Survival (EFS). Cox proportional hazard models were used to estimate hazard ratios, adjusted for potential confounders. Results A total of 345 tumours (29%) were luminal A, 558 (46%) luminal B, 107 (9%) HER2 luminal, 76 (6%) HER2 enriched and 116 (10%) TN. At a median follow-up of 58 months (4-137 months) relapse events occurred in 38 (11%) patients with luminal A, 102 (18%) with luminal B, 33 (31%) with HER2 luminal, 32 (42%) with HER2 enriched and 40 (35%) with TN tumours. Cox proportional hazard multivariable analysis identified the following independent associations with EFS in each subtype: ≥4 positive axillary nodes (HR 4.96, 95% CI 1.97-12.48, p<0.001), tumour grading=3 (HR 2.97, 95% CI 1.00-8.79, p<0.049), adjuvant radiotherapy (HR 0.46, 95% CI 0.22-0.95, p<0.035) in luminal A tumours; ≥4 positive axillary nodes (HR 3.97, 95% CI 2.34-6.74, p<0.001), PgR<20% (HR 1.55, 95% CI 1.04-2.29, p<0.03), age at first diagnosis >35 years (HR 0.22, 95% CI 0.10-0.48, p<0.001), adjuvant hormonotherapy (HR 0.43, 95% CI 0.22-0.85, p<0.01), adjuvant radiotherapy (HR 0.57, 95% CI 0.36-0.91, p<0.02) in luminal B tumours; ≥4 positive axillary nodes (HR 5.22, 95% CI 1.91-14.28, p<0.001) and adjuvant trastuzumab (HR 0.41, 95% CI 0.17-0.95, p<0.039) in HER2 enriched, ≥4 positive axillary nodes in HER2 luminal (HR 4.78, 95% CI 1.84-12.39, p<0.001) and TN (HR 4.12, 95% CI 1.96-8.65, p<0.001) tumours. Conclusion Conventional risk factors retain their independent value in a subtype-specific fashion in early breast cancer. Although growing importance is being given to stratification based on biological characteristics, the integration of traditional factors facilitates a better definition of risk categories in early breast cancer patients. Citation Format: Valentina Rossi, Paola Berchialla, Ivana Sarotto, Furio Maggiorotto, Nicoletta Tomasi Cont, Riccardo Ponzone, Massimo Aglietta, Filippo Montemurro. Do traditional prognostic factors in early breast cancer still have a role in the molecular era? [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-49.