OBJECTIVES To study 17 cases of secondary syphilis that progressed to neurosyphilis despite appropriate treatments and whose rapid plasma reagin (RPR) titres showed a fourfold decrease within 6 months but did not revert to negative. METHODS Secondary syphilis patients with the following criteria were analysed: (1) RPR titres declined fourfold within 3 months after therapy, (2) patients denied high-risk sexual behaviours following treatment, (3) RPR titre remained serofast 24 months after treatment, (4) reactive cerebrospinal fluid (CSF)-venereal disease research laboratory (VDRL) and CSF-Treponema pallidum Particle Agglutination Test (TPPA) and (5) HIV antibody negative. RESULTS 14 male and three female patients met the criteria. 13 patients were asymptomatic. The CSF leucocyte count was elevated in 10 patients of whom nine also had elevated CSF-proteins. The RPR titres following secondary syphilis treatments were ≥ 1:32 in five cases, 1:16 in four cases, 1:8 in six cases and 1:4 in two cases. Following treatments for neurosyphilis, four cases with neurological or psychiatric manifestations resolved or improved, nine cases with raised CSF-white blood cells returned to normal and nine of 12 cases with raised CSF-protein declined to normal. CONCLUSIONS Neurosyphilis may be detected in immunocompetent patients despite appropriate therapy for early-stage syphilis and appropriate serological responses. Clinicians should consider a CSF examination in any treated patient with evidence of disease progression irrespective of prior treatment history and serological response.