Different variants of the cell adhesion molecule CD44 have been involved in malignant transformation and cancer metastasis. In the present investigation we assessed the preoperative serum levels of soluble CD44 standard (sCD44-st), sCD44 splice variant 5 (sCD44-v5), and sCD44 splice variant 6 (sCD44-v6) in 51 patients with ovarian cancer. Median preoperative sCD44-st, sCD44v5, and sCD44-v6 levels were 417 ng/ml (range, 240- > 602 ng/ml), 78 ng/ml (range, 5-314 ng/ml), and 86 ng/ml (range, 1-243 ng/ml), respectively. No significant relationship was detected between sCD44-st concentrations and the common clinicopathological variables. Conversely, sCD44-v5 and sCD44-v6 levels were significantly lower in FIGO stage III-IV than in stage I disease (p < 0.0001 and p = 0.001, respectively). Moreover, with regard to advanced ovarian cancer, sCD44-v5 levels were lower in patients with poorly differentiated (G3) than in those with moderately (G2) or well (G1) differentiated tumors (p = 0.038), as well as in patients whose residual disease was > 2 cm than in those with smaller residuum (p = 0.025). Similarly, sCD44-v6 levels were lower in patients with large residual disease (p = 0.05). The median value of serum sCD44-v6 was lower in patients with G3 than in those with G1-G2 tumor, but the difference was not significant. In conclusion, sCD44-st, sCD44-v5, and sCD44-v6 are detectable in sera from patients with epithelial ovarian cancer. A reduction in preoperative sCD44-v5 and sCD44-v6 levels seems to be associated with advanced, poorly differentiated tumors and with large residual disease after first surgery, and it might reflect an increased biological aggressiveness of the malignancy.