Mycosis fungoides (MF) is characterized by a switch from indolent behaviour in the early stages to a worse clinical outcome in the advanced ones. Recently, various studies have investigated the role the microenvironment might play in such a switch. We have analysed the distribution of Langerhans cells, plasmacytoid dendritic cells and myeloid-derived suppressor cells in 46 MF cases in various stages, aiming to assess whether changes occur from early to advanced stage. We have investigated the number of langerin, CD303 and arginase-1 positive cells and their distribution at high power. Data were analysed using t test for continuous variables, chi (2) tests or Fisher's exact test for categorical variables, as well as analysis of covariance. In comparing stages IA/B to IIB, we observed a significant decrease in Langerhans cells (p value 0.03) and a significant increase in CD303 and arginase-1 positive cells (p value < 0.01 for both markers). Furthermore, a significant increase in Langerhans cells only was observed in stage IIB in comparison to stage III (p = 0.02), while in stage IV, a significant decrease in Langerhans cells was noted in comparison to stage III (p = 0.02). Our data suggest that changes in the microenvironment might influence disease progression, especially from stages IA/B to IIB, opening new scenarios in MF therapy.