Surgery is the main treatment for renal cell carcinoma (RCC); nephron sparing surgery can be performed as a treatment of choice for small peripheral lesions. Epigenetics configures a new entity that regulates gene expression throughout methylation, acetylation and chromatin remodelling. In addition to silencing as a result of mutations, loss of heterozygosity, or classic genetic events, epigenetic modification symbolizes essential events during carcinogenesis and tumour development. We investigated global methylation and histone acetylation expression in a series of small conventional clear cell renal carcinomas (i.e. less than 5 cm) (pT1a) treated with partial nephrectomy, to assess their possible role as diagnostic biomarkers. A total of 54 patients with conventional single RCC were selected and treated with partial nephrectomy; they were followed up to 186 months. Immunohistochemistry was performed on paraffin-embedded sections, using anti-5-methylcytosine (5mc) and anti-Acetyl-Histone H3 (Lys 9). Our results confirm that the mean percentage of global cellular methylation in tumoural tissue was significantly higher compared to healthy peritumoural tissue, whereas the mean percentage of histone cellular acetylation in tumoural tissue was significantly lower. The percentage of methylation was significantly higher in grades 3 and 4 (P = 0.033), whereas the percentage of histone acetylation was significantly lower (P = 0.023), suggesting therefore that these markers could correlate with tumour aggressiveness in pT1a RCC. On univariate analysis of patient survival in relation to the different considered factors, Fuhrman grade was the most important survival factor. These epigenetic markers can give us interesting information about chromatin remodelling in RCCs; the percentage of global methylation increases with increasing Fuhrman grade, whereas histone acetylation decreases with increasing grade in small RCC; our results suggest that global hypermethylation and histone hypoacetylation can be assumed to be an early event in RCC and to correlate with tumour aggressiveness.