EMBARK demonstrated prolonged metastasis-free survival with enzalutamide ± leuprolide versus leuprolide alone for patients with high-risk biochemical recurrence of prostate cancer, with health-related quality of life (HRQoL) maintained. To evaluate treatment effects on sexual activity (SA), item-level analyses of SA-related HRQoL were performed. HRQoL was assessed (baseline, every 12 wk) until metastasis or death. Time to confirmed clinically meaningful deterioration (TTCD; confirmed at next visit) and longitudinal changes in HRQoL were examined using Cox regression and mixed-model repeated measures analyses, respectively. In comparison to leuprolide alone, enzalutamide monotherapy delayed TTCD in interest in sex (8.5 vs 5.6 mo; hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.57-0.87; p < 0.001), extent of SA (5.7 vs 3.0 mo; HR 0.69, 95% CI 0.54-0.90; p = 0.004), satisfaction with sex life (11.1 vs 5.4 mo; HR 0.61, 95% CI 0.45-0.84; p = 0.001), and erectile function (5.5 vs 2.9 mo; HR 0.67, 95% CI 0.50-0.88; p = 0.003). TTCD in SA-related HRQoL was similar with enzalutamide + leuprolide and leuprolide alone, except TTCD in erectile function was shorter by a statistically significant median of 0.1 mo (3 d), which is not clinically meaningful. Longitudinally, no clinically meaningful changes for any SA-related item were observed from baseline to week 205 in any group. SA-related HRQoL preservation seems to be better with enzalutamide monotherapy than with leuprolide alone.