Multiple past studies have reported a reduced risk of breast cancer-related mortality (BCM) in relation to pre-diagnostic use of hormone therapy (HT); however, the extent to which this reduction is due to heightened screening or tumor biology is unknown. Using a population-based cohort of 1,911 post-menopausal women diagnosed with invasive breast cancer at ages 45-79 from 1993 to 1999, we investigated the extent to which the reduced risk in BCM observed in relation to HT might be explained by screening patterns or tumor features. Estrogen-progestin therapy (EPT) use was associated with a decreased risk of BCM (after adjustment for age, study, mammography, stage, and treatment), but only among older women (ever use: ≥ 65 years: HR = 0.45 [95% CI 0.26-0.80]; <65 years: HR = 1.03 [95% CI 0.60-1.79]). Estrogen-alone therapy (ET) use was not associated with risk of BCM (ever use: ≥ 65 years: HR = 0.76 [95% CI 0.51-1.12]; <65 years: HR = 1.20 [95% CI 0.71-2.02]). HT users had a much greater frequency of mammography (P value <0.001). EPT use was associated with tumor characteristics related to improved prognosis in older women after adjustment for screening, including an inverse association with poorly differentiated tumors (OR = 0.57 [95% CI 0.38-0.85]) and an association with lobular tumors (OR = 1.68 [95% CI 1.07-2.65]). Beyond the influence of EPT use on screening uptake, these data indicate that the improved survival associated with pre-diagnostic EPT use may be due in part to the development of more favorable tumor characteristics.