Background: After decades of use,menopausal hormone therapy influence on ovarian and endometrial cancer remains unsettled. Therefore, we assessed the long-term influence of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and CEE-alone use on ovarian and endometrial cancer incidence and mortality in long-term follow-up of the Women’s Health Initiative randomized, placebo-controlled clinical trials. Methods: Long-term follow-up of two placebo-controlled randomized clinical trials that recruited 27,347 postmenopausal women aged 50-79 years without prior breast cancer or invasive cancer within 10 years (and no baseline endometrial pathology in combined hormone trial participants) from 40 US centers from 1993-1998. In 16,608 women with a uterus, 8,506 were randomized to daily 0.625 mg/d of CEE plus 2.5 mg/d of MPA and 8,102, placebo. In 10,739 women with prior hysterectomy, 5,310 were randomized to daily 0.625 mg/d of CEE-alone and 5,429, placebo. Intervention was stopped for cause before the planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE-alone). Cancers were verified by central pathology report review. Mortality findings were enhanced by serial National Death Index (NDI) queries. The primary study outcomes were ovarian cancer and endometrial cancer incidence and related mortality. Results: After 20-year follow-up, with mortality information for > 98%; in the initial WHI report on CEE-alone influence on ovarian cancer, CEE-alone, versus placebo, significantly increased ovarian cancer incidence (35 cases [0.041% annualized rate] vs 17 [0.020%]; hazard ratio [HR], 2.04; 95% CI 1.14-3.65; P = 0.01) and ovarian cancer mortality (HR 2.79 95% CI 1.30-5.99, P = 0.006). KM-estimates and cumulative hazard ratios indicate a persistent CEE-alone adverse effect on ovarian cancer incidence that emerged after 12-years follow-up and did not diminish (P = 0.006). In contrast, use of CEE plus MPA, versus placebo, did not increase ovarian cancer incidence (75 cases [0.051%] vs 63 [0.045%]; HR, 1.14; 95% CI, 0.82-1.59; P = 0.44) or ovarian cancer mortality (HR 1.21 95% CI 0.84-1.74). CEE plus MPA did significantly lower endometrial cancer incidence (106 cases [0.073%] vs 140 [0.10%]; HR, 0.72; 95% CI, 0.56-0.92; P = 0.01), without statistically significant influence on endometrial mortality (HR 0.58 95% CI 0.29-1.16) Conclusions: In randomized, placebo-controlled, clinical trial settings, CEE-alone, in women with prior hysterectomy, significantly increased ovarian cancer incidence and increased ovarian cancer mortality while CEE plus MPA, in women with a uterus, in contrast to most observational studies, did not. However, CEE plus MPA reduced endometrial cancer incidence. These findings inform decisions regarding menopausal hormone therapy use. Clinical trial information: NCT00000611.