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Previously the basic helix-loop-helix transcription factor termed heart- and neural crest derivatives-expressed protein 2 (Hand2), was identified as regulator of morphogenesis in a variety of tissues. There are reports that in the uterus Hand2 is induced by progesterone. Embryo implantation and decidualization of stromal cells are critical events in the establishment of successful pregnancy. Correct spatio-temporal activity of steroid hormones, estrogen (E) and progesterone (P) is vital for these events. The physiological effects of P are mediated by interaction with two progesterone receptors (PRs), PR-A and PR-B. PRs are members of the nuclear receptor superfamily of transcription factors. This study was undertaken to analyze the effects of E and P on Hand2 expression in the uterus of wild type and genetically modified mice lacking both PRs and only the PR-A isoform. To analyze the role of PRs in Hand2 expression ovariectomised mice were treated with oil, E, EP and P and uterine tissue was analyzed for expression of PR and Hand2. Our results indicate that Hand2 expression is regulated by E and P. We also analyzed Hand2 expression during early pregnancy. Double labeling immunofluorescence and quantitative PCR were used to analyze spatio-temporal expression of PR and Hand2 in mouse uterus on day 2.5, 4.5 and 7.5 of pregnancy. We found that although high levels of PRs are present on day 2.5 of pregnancy we did not detect Hand2 before implantation. On day 4.5 of pregnancy Hand2 co-localize with PR expressing cells. At this stage Hand2 expressing cells are localized mainly in the uterine stroma underlying the luminal epithelium (LE). Decidualisation is prominent at day 7.5 of pregnancy and in decidual cells PRs and Hand2 remain co-localized. The Hand2 positive cells are spatially segregated mainly in antimesometrial side.