Background: Pembrolizumab/axitinib (PAXI) combination is an approved option as first-line therapy of mRCC. The aim of this analysis is to evaluate safety profile of PAXI combo in the real-world experience in Italy. Methods: This is a prospective study including patients (pts) diagnosed with mRCC who received PAXI as first-line therapy in recruiting Italian Centers. Safety data about clinically significant adverse events (AEs), defined as AE requiring corticosteroids, hormone replacement, drug delay, discontinuation or dose reduction were collected. Results: Data from 122 pts treated from January 2021 to September 2022 have been analyzed. With a median follow-up of 10 mos (range 0.2 - 21) and treatment interruption in 35 pts (29%), at landmark 6-mos and 12-mos the treatment was ongoing in 76% (95%CI 0.67-0.83) and 66% of pts (95%CI 0.56-0.75) respectively. In 11% of pts a starting dose of Axi <5mg was reported (8% higher starting dose). 2% of pts experienced Axi dose titration while 37% of pts had a dose reduction. Pts completed a mean of 10 (1 - 31) cycles of Pembro. Toxicity led to treatment discontinuation in 20% (7/35) of cases. Clinically significant AEs occurred in 61% of pts (74), managed with corticosteroids use in 32% (24/74) of pts, hormone replacement (mainly levothyroxine) in 11% (8/74), drug delay in 64% (47/74), discontinuation in 41% (30/74) or dose reduction 18% (13/74). When required, the most used steroid was prednisone (48%) following by dexamethasone (22%), prednisolone (17%), methylprednisolone (13%). Grade 3-4 clinically significant AEs occurred in 25% (18) and 3% (2) of pts respectively, with hepatic injury 33% (6/18) and hypertension 17% (3/18) as the most common reported G3 events. The two G4 AEs reported were pancreatitis and hepatic injury. No treatment-related deaths emerged. In 20% of cases AE were related to Pembro and in 47% of cases to Axi, in 14% to both drugs. In 28% of pts (34/122) a second clinically significant AE occurred, requiring corticosteroids 27% (9/34), hormone replacement 9% (3/34), drug delay 59% (20/34), discontinuation 41% (14/34) or dose reduction 21% (7/34). Grade-3 clinically significant AEs occurred in 29%, with hepatic injury and hypertension (both 3 pts) as the most common events. No grade 4 AEs were reported. The second AE in 21% of cases was related to Pembro and in 59% of cases to Axi, in (9%) to both drugs. Conclusions: PAXI combination had a tolerable safety profile in mRCC, with few high-grade clinically significant AEs, no new toxicities were identified.