Background: The immuno-oncology (IO) therapy combination nivolumab + ipilimumab, and the IO-tyrosine kinase inhibitor (TKI) combination pembrolizumab + axitinib, received US FDA approvals in 2018 and 2019, respectively, as first-line (1L) therapy for advanced renal cell carcinoma (aRCC). We examined physician perceptions of concerns about and barriers to 1L treatment by class of regimen (IO-IO, IO-TKI, and single-agent TKI [SA-TKI]) in the United States. Methods: US-based oncologists treating ≥ 5 aRCC patients in the prior 12 months were identified from the Cardinal Health network, a community of > 800 oncologists. Physicians were surveyed about concerns in prescribing and barriers to treating by class (scale of 1–5; 1 = no concern/not a barrier, 5 = most concerning/major barrier); mean scores are reported. Adverse events (AEs) of concern were selected from a prespecified list and respondents rank-ordered from most to least concerning by class. Physicians were also asked to gauge affordability and to rank-order 13 characteristics to identify key factors in prescribing preference. The impact of COVID-19 on aRCC care in practice was also assessed. Results: A total of 49 providers (84% community, 16% academic) treating a median of 20 (IQR 14–30) aRCC patients from across the United States participated. For IO-IO, the top 3 concerns in prescribing were AEs (4.3), patient out-of-pocket costs (OOP; 3.7), and unexpected late AEs (3.6), whereas patient OOP (4.3), AEs (4.1), and patient adherence (3.9) were of most concern for IO-TKI. For SA-TKIs, the top 3 concerns were patient adherence (3.9), patient OOP (3.9), and AEs (3.6). High patient OOP and impact on quality of life were the top 2 barriers in using IO-TKI therapy. The most concerning AEs were colitis, pneumonitis, and hypertension for IO-IO or IO-TKI, and diarrhea, fatigue, hand-foot syndrome, and hypertension for SA-TKI. Overall survival (OS), progression-free survival (PFS), and complete response (CR) were ranked 1st, 2nd, and 3rd factors in prescribing preferences while patient compliance, patient preference, and practice reimbursement ranked 11th, 12th, and 13th. Patient OOP and drug acquisition costs (DAC) were the most important factors when considering the affordability of treatment, with the perception that IO-IO was the most expensive among the classes of therapy. The overall impact of COVID-19 on caring for aRCC patients was very limited, with a moderate increased use of telemedicine and a slight impact on the timing and number of routine care visits. Conclusions: OS, PFS, and CR ranked highest among the most important factors influencing selection of 1L treatment for aRCC. Factors of concern and barriers varied by class of treatment, with patient adherence and OOP affecting use of TKI or IO-TKI therapies, and AEs affecting the use of IO-based therapy. This study revealed perceptions of high patient OOP and DAC of IO-IO therapy, in contrast to our expectations.