Interferons (IFNs) are used widely in the treatment of viral infections, tumours and neurological disorders. The aim of this study was to evaluate the endogenous expressions of various IFN-induced compounds [specifically: neopterin (NPT), beta2microglobulin (β2mg) and 2–5 oligoadenylate synthetase (2–5 OAS)] in patients with various chronic diseases requiring treatment with IFN type I. The results showed that patients with such chronic diseases as hepatitis C virus-associated type II mixed cryoglobulinaemia (MC), chronic hepatitis C (CHC) and relapsing–remitting multiple sclerosis (RRMS) are characterized by different activations of the IFN system. Furthermore, the interindividual variability in baseline levels of IFN-induced biomarkers was higher in patients with chronic diseases than in healthy individuals. When levels of the above biomarkers were measured 24 h after the first injection of IFN in patients with CHC or RRMS, significant increases in expression levels of IFN-induced compounds were recorded but, again, there is a broad range of variability in the degree of increase. Further, a significant inverse correlation between baseline levels of NPT, β2mg and 2–5 OAS activity and their relative increases after IFN administration was found in patients with CHC or RRMS. Together, the results are consistent with the observation that there is considerable interindividual heterogeneity in the clinical response to IFNs, which suggests that host factors other than disease markers must be taken into account in order to manage and optimize the IFN therapy.