The objective of our study was to evaluate the usefulness of immunohistochemical (IHC) staining techniques in the etiological diagnosis of non-immune hydrops fetalis (NIHF). The records of all 1,098 autopsies performed between January 1987 and May 2008, by the Division of Fetal Pathology of the University of Genoa, were reviewed and all 79 fetuses diagnosed with NIHF were re-evaluated. Additional IHC staining using antibodies that specifically stain blood and lymph vessels (CD31, CD34, smooth muscle actin antibody, D2-40) were performed. Results were compared to results from the literature. Our results showed that in 67/79 cases, evaluation by standard autopsy protocol led to an etiologic diagnosis. Furthermore, we were able to identify the pathogenetic mechanisms that eventually caused NIHF in 42/79 cases. Adding IHC staining to all evaluations identified the pathogenetic mechanism in a further 17 cases (total 59/79 cases). Lymphatic dysplasia was diagnosed by standard autopsy protocol in 1/79 (1.3%), while adding IHC staining resulted in 18/79 (22.8%) cases being diagnosed (P = 0.0001). The present rate of 22.8% of lymphatic dysplasia in non-immune hydrops fetalis is significantly higher than reported in the literature (36/818 or 4.4%; P = 0.01). In conclusion, specific IHC staining techniques aimed at detecting lymphatic dysplasia are needed and should be mandatory in autopsies of fetuses with non-immune hydrops fetalis. © 2010 Wiley-Liss, Inc.