Background: Novel anti-androgen hormonal therapies (NAHTs) for advanced prostate cancer (PC) are mainly oral with an overall good toxicity profile and offer the convenience of home administration and reduced hospital footfalls. This imposes the burden of self-administration, often unsupervised, on a population of elderly patients overwhelmed by the assumption of many other concomitant medications. Therefore, lack of treatment adherence is becoming an increasingly social and health issue. Methods: In a prospective observational cohort study, metastatic castration-resistant PC (mCRPC) patients aged ≥70 years receiving abiraterone (ABI) or enzalutamide (ENZ) were enrolled in six Italian centres of the Meet-Uro network and monitored for their treatment adherence. Monitoring included pill counting, self-assessment questionnaire and clinical diaries at each clinical visit. Non-adherence rates were based on proportions of missed/prescribed pills ratios by pill counting as an overall estimate or the median of individual values. Results: Overall, 234 pts were recruited (median age: 78 years [73-82], 86 were treated with ABI and 148 with ENZ; 69% of the pts received NAHT in the pre-chemotherapy setting, while 24% in the post-chemo and 6% had the two treatments consecutively. Pts were monitored for adherence for a median time of seven cycles [IQR:4-12]. The two arms were well balanced for all baseline characteristics, besides steroids use (100% vs 9%, p < 0.001), as ABI requires steroids, and Charlson score, whose range was higher for ENZ pts than ABI pts (range 10-12 vs 8-11, p = 0.028). Overall, the percentage of non-adherence was higher for ABI than ENZ (5.2 vs 4.2 missed/prescribed pills, p < 0.001). After Bonferroni correction, geriatric G8 score correlated with non-adherence (p = 0.004, r = 0.18). Pts on ENZ tended to report missing pills more frequently than ABI pts, and the reason for non-adherence was forgetfulness (42% vs 17%, p < 0.001). A third of pts never completed the clinical diary given at each cycle. Overall survival (OS) within the study was 48.8 months. However, patients on ABI had a longer progression-free survival (PFS) compared to pts treated with ENZ (median PFS 28.4 [24.2-32.5] vs 23.1 [18.2-28.1] months, p = 0.041). Conclusions: Physicians tend to treat elderly and frailer people with ENZ. mCRPC patients on ENZ are more adherent to treatment, with forgetfulness being a potential barrier. Nevertheless, OS and PFS were consistent with those from ABI and ENZ pre-chemo registration studies, with ABI conferring a longer PFS in our study population.