A case-control study was performed in order to determine whether expression of the progesterone receptor (PR) and/or aberrations of the PR gene contribute to the development of recurrent endometrial carcinoma. Primary tumours from 44 patients with recurrence of stage I endometrial carcinoma (patients) within 3 years after initial treatment were compared with tumours from 44 matched patients who were free of recurrence for a minimum of 3 years (controls). Paraffin wax-embedded primary tumours (n = 88) and recurrent tumours (n = 32) were analysed immunohistochemically for PR expression. A staining index (SI = 0-9) based on the staining intensity and the number of stained cells was calculated. DNA extracted from paraffin wax-embedded tissues was subjected to PCR-restriction fragment length polymorphism analysis (PCR-RFLP) for determination of the PROGINS DNA sequence alterations and the +331G/A-promoter polymorphism. Low PR expression (SI < 1.0) was observed in 7% of primary tumours derived from controls, 25% of primary tumours from patients with recurrence, and 38% of recurrent tumours. The expression of PR was significantly lower in primary tumours from patients with recurrence (SI = 4.0 +/- 0.5) than in the tumours in the control group (SI = 5.6 +/- 0.5) (T-test for paired analysis, p < 0.05). The PROGINS and +331G/A-promoter polymorphism were not related to age at diagnosis, tumour grade or myometrial invasion. The +331G/A-promoter polymorphism was present in 14% of primary tumours from patients without recurrence, compared with 17% of patients with recurrence. The PROGINS polymorphism was observed in 16% of primary tumours from patients without, and in 34% of patients with, recurrence (OR 2.6; 95% CI: 0.9-7.6). Most interestingly, patients who carried the PROGINS variant and in whom a PR-expressing tumour was diagnosed were at significantly enhanced risk of relapse (OR 4.7; 95% CI: 1.3-17.1). In conclusion, low PR expression tended to be associated with recurrent disease, and PR expression in tumours from patients carrying the PROGINS allele was predictive of the risk of recurrence.