Background: Sexual activity is an important part of social functioning and quality of life. Cancer diagnosis and concomitant treatment has a damaging effect on sexual function. The objective of this prospective study was to evaluate the incidence of erectile dysfunction (ED) in men with metastatic renal cell carcinoma (mRCC) receiving first-line therapy. Methods: All patients were evaluated for erectile function with the 5-item version of the International Index of Erectile Function (IIEF-5) and Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) before first and after four cycles/months of the first-line therapy with nivolumab plus ipilimumab (IO-IO), pembrolizumab plus axitinib/lenvatinib (IO-TKI) or sunitinib, pazopanib and cabozantinib (TKI). Results: Two hundred eighty-two male patients with mRCC were enrolled. Median age was 60.5 years (range 39–71 years) and 164 (58%) patients had at least one cardiovascular risk factor. Sixty-seven (24%) patients had favorable IMDC risk, 208 (74%) had ECOG ≤1, 214 (76%) had ≥2 organs with metastases, and 11 (4%) had non-clear cell mRCC. All patients were treated with IO-IO (32%), IO-TKI (26%), and TKI (42%). At baseline, IIEF-5 mean score was 17 (SD, 2.9) in ITT population. Patients with 2 and more IMDC risk factors had a lower IIEF-5 mean score (13; SD, 1.4). 182 (64.5%) patients reported a negative change in their sexual life since the start of the therapy. 90 (32%) patients had no sexual activity. After four treatment cycles/months IIEF-5 mean score reduced to 9 (SD, 3.5), which was statistically significant (P<0.0001). The IIEF-5 scores were associated with type of anticancer treatment, with the minimal change observed in IO-IO group (P=0.2) and highest change in TKI group (P<0.0001). A correlation was no found between FKSI-19 and IIEF-5 scoring systems. Conclusions: A prospective assessment in a large group of male mRCC patients revealed mild ED (17/25) in previously untreated patients and moderate ED (9/25) after four cycles/months of first-line therapy, especially in patients receiving TKIs. These changes did not correlate with kidney symptom index.