It is believed that oxidative stress plays a role in the development and progression of renal cell carcinoma (RCC). Identifying oxidative and nitrosative modifications in proteins and defining their roles in clear cell RCC (ccRCC) may be helpful in the elaboration of targeted therapeutic approaches to mitigate protein damage. The study aimed to investigate the status of oxidative/nitrosative stress and to explore its role in development and progression. The studied group consisted of 48 newly diagnosed ccRCC and 30 healthy controls. Serum levels of oxidative stress markers, such as advanced oxidation protein products (AOPPs), thiol groups, Amadori products, 3-nitrotyrosine, nitrate/nitrite, malondialdehyde (MDA), 4-hydroxy-2-nonenal, and total antioxidant capacity (TAC), were determined. Additionally, associations between tumor stage assessed according to TNM classification, histological grade, and the effect of the presence of angioinvasion on the level of stress markers were evaluated. The levels of Amadori products, 3-nitrotyrosine, and nitrate/nitrite were elevated, while the levels of thiol groups and TAC decreased in the ccRCC group. The levels of AOPP, Amadori, and 3-nitrotyrosine increased, and thiol group and TAC levels decreased with the increasing clinical stage of the tumour. In the case of the advanced histological assessment of the tumour, we found decreasing levels of thiol groups and increasing levels of MDA. In patients with angioinvasion, nitrate/nitrite and MDA levels were significantly elevated in those without angioinvasion. Moreover, we found weak significant positive correlations of AOPP and MDA with age. Furthermore, the concentration of thiol groups and the TAC were inversely correlated with age. Surprisingly, there was not any correlation between markers of oxidative stress and sex of patients and their body mass index. Oxidative stress increased with the progression of the disease assessed according to the TNM and histological grade. These results demonstrate systemic oxidative stress in ccRCC, suggesting the therapeutic application of antioxidants.