Evidence of immune activation has occasionally, but not consistently, been reported in schizophrenia. Investigations of cytokine abnormalities in serum, and occasionally in CSF, have yielded inconsistent results, which have been difficult to resolve. In such studies, schizophrenia has been assumed to consist of a single process rather than a group of disorders. This study assesses differences in the pro-inflammatory cytokine, interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) in two previously delineated subtypes of schizophrenics ("delayed-responders"(DR) (n=23) and "poor-responders" (PR) (n=8)) during periods of neuroleptic-free psychotic exacerbation, and in a comparison group of normal controls (n=14). The two response subtypes were separated by subsequent treatment response (greater/less than 60% reduction of SAPS scores from baseline during 6 months of systematic treatment). The IL-6 assay, a sandwich enzyme-linked immunosorbent assay, was sensitive and reliable to detect IL-6 levels in the CSF of all subjects. CSF IL-6 was found to be significantly higher in the DR than the PR (P=0.017) and the controls (P=0.013). In addition to supporting the concept of heterogeneity in schizophrenia, this study also provides evidence that a central immune process may be occurring centrally in one subtype of schizophrenia.