Insulin-like growth factor-I (IGF-I) is known to be involved in the development and progression of several types of solid tumors including ovarian cancer. IGF-I levels in local tissue is subject to both endocrine and paracrine/autocrine regulation. To investigate which regulation is more importantly involved in IGF-I action in ovarian cancer regarding tumor progression, we analyzed IGF-I mRNA expression (assuming only from paracrine/autocrine regulation) and peptide concentration (subject to both endocrine and paracrine/autocrine regulation) as well as a genetic polymorphism (CA dinucleotide repeats) in 215 epithelial ovarian cancer patients. Genomic DNA, total RNA and cytosol proteins were extracted from fresh tumor samples. Two alternatively spliced IGF-I transcripts (IGF-IA and IGF-IB) were analyzed using real-time PCR. Cytosol levels of free and total IGF-I were measured with enzyme-linked immunosorbent assay. DNA sizing analysis was performed to determine the CA polymorphism. The study showed that the CA polymorphism had a weak influence on IGF-I expression, but no effect on tumor progression. High levels of free, not total, IGF-I peptide were associated with elevated risk of disease progression (HR = 2.06; 95%CI: 1.22-3.50), and the association was independent of clinicopathologic features of the disease. One of the IGF-I transcripts (IGF-IA) had a similar but less significant impact on disease progression. Women with high IGF-I mRNA and peptide were at greater risk for disease progression compared to those with low in both (HR = 2.13; 95%CI: 1.13-3.95). These findings support the notion that IGF-I is involved in ovarian cancer progression and free IGF-I plays a more important role in the disease. The study also suggests that both endocrine and paracrine/autocrine are involved in the regulation of IGF-I activity in ovarian cancer.