The potential use of a 35 kDa inter-alpha trypsin inhibitor H4 fragment (ITIH4f) as a cancer biomarker was unveiled when it was detected in sera of patients with breast cancer using gel-based proteomic analysis and a lectin that binds O-glycosylated glycoproteins. Subsequent studies showed that the serum ITIH4f was also of relatively higher abundance in patients with endometrial and ovarian cancer (germ-line and epithelial ovarian carcinoma) but not in patients with nasopharyngeal carcinoma, osteosarcoma (localized disease) and cervical cancer (squamous cell cervical carcinoma and cervical adenocarcinoma). One of the differences between the types of cancer that are associated with increased abundance of serum ITIH4f with those that did not is that the former is associated with enhanced levels of serum oestrogens. This suggests that release of ITIH4f is oestrogen-induced, and the hypothesis was further substantiated when sera of healthy pregnant women and patients with hydatidiform mole, whose serum oestrogen levels were elevated, were shown to contain relatively higher levels of serum ITIH4f than controls. In this seminar, the pros and cons of ITIH4f as a cancer biomarker will be discussed.