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Purpose: The current randomized, double-blind, placebo-controlled clinical trial addressed the effects on penile erectile function of relatively high daily oral doses (6 g/day) of l-ARG for 3 months (N= 51) compared to placebo (N= 47), in patients with vasculogenic ED, with comparison between mild–moderate and severe vasculogenic ED. Methods: The outcome measures included IIEF-6 score and cavernous arteries peak systolic flow velocity (PSV) at dynamic penile duplex ultrasonography (PDU). Results: l-ARG supplementation for 3 months significantly increased IIEF-6 score in the overall cohort (p< 0.0001) and in subgroups of patients with mild–moderate (p< 0.0001) and severe (p= 0.007) vasculogenic ED; PSV was significantly increased in the overall cohort (p< 0.0001) and in patients with mild–moderate (p< 0.0001), but not severe vasculogenic ED. At study completion, 74% of patients improved ED degree category, although only 24% of patients, mainly belonging to the baseline category of mild ED, reached IIEF-6 scores compatible with absence of ED; moreover, 20% of patients, exclusively belonging to the baseline category of mild–moderate vasculogenic ED, reached PSV values compatible with absence of ED. Conclusion: The results of the current study demonstrated that supplementation with relatively high doses of l-ARG as a single compound for 3 months significantly improved penile erectile function, assessed by both IIEF-6 score and PSV at dynamic PDU in patients with mild–moderate, and improved IIEF-6 score, but not PSV, in patients with severe vasculogenic ED, therefore suggesting that l-ARG might be an alternative treatment in mild–moderate vasculogenic ED patients experiencing adverse effects or with contraindications for chronic treatment with PDE5i compounds.