Background: Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer spanning more than 20 years, but the biological factors influencing this risk are unknown. Here we aimed to investigate the long-term survival and benefit from tamoxifen therapy for patients with Luminal A and Luminal B subtype tumors. Methods: The Stockholm Tamoxifen (STO-3) trial enrolled 1780 postmenopausal patients from 1976 until 1990 with lymph node-negative breast cancers and tumors less than or equal to 30 mm in diameter, randomly assigned to at least two years of adjuvant tamoxifen (40 mg daily) vs no adjuvant treatment. All patients had a complete long-term follow-up until December 31, 2012, and detailed patient and clinical information. Gene expression data was generated using custom designed Agilent arrays from FFPE breast cancer tumor tissue and was used to define Luminal A and Luminal B subtype tumors. ER, PR, HER2 and Ki-67 were also reassessed in 2014. Long-term breast cancer-specific survival was performed using Kaplan-Meier analysis and flexible parametric survival models were used to estimate the time-varying hazard ratios (HRs) adjusting for patient and tumor characteristics. Results: A statistically significant difference in long-term survival (25 years) by Luminal subtype and trial arm was seen (Log Rank, P < 0.0001). For Luminal A and Luminal B patients, the 25 year survival was 88% versus 69% for treated patients and 73% versus 58% for untreated patients. Luminal A patients in the tamoxifen treated arm had a significantly reduced long-term risk of fatal breast cancer up to 20 years after breast cancer diagnosis (HR at 15-years: 0.59; 95% CI, 0.35-0.98; and HR at 20-years: 0.65; 95% CI, 0.32-1.30) as compared to the untreated arm. However for patients with Luminal B tumors, a significantly reduced long-term risk was only seen up to 10 years after diagnosis (HR at 5-years: 0.37; 95% CI, 0.18-0.73; and HR at 10-years: 0.68; 95% CI, 0.31-1.47). Conclusions: Patients with Luminal A subtype tumors have a long-term benefit from tamoxifen therapy, whereas the benefit for patients with Luminal B tumors is up to ten years after diagnosis. Clinical trial information: STO-3 trial from 1976 no registration# at the time.