Background Cognitive deficits are a central feature of schizophrenia but it is not certain how cognitive functioning changes over time. The purpose of this prospective longitudinal study was to determine the temporal change of cognitive functioning and the predictors of cognitive performance from among demographic, clinical, and biological variables. Methods Participants were individuals with schizophrenia or schizoaffective disorder whose cognitive functioning was assessed at multiple time points with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). At the baseline visit participants had a blood sample drawn from which C-reactive protein, antibodies to Herpes Simplex Virus type 1, and selected genetic polymorphisms were measured. Repeated measures linear regression was used to determine whether cognitive measures changed over time and which variables predicted cognitive performance. Results The sample consisted of 132 participants, mean age 43.7years at baseline, who received a median of 3 cognitive assessments over a period averaging 2.8years. The RBANS Total score and Language index showed no statistically significant temporal change; performance on two indices, Immediate Memory and Attention, showed modest but statistically significant improvements (gains of 0.89±0.33 and 0.76±0.29 points per year, respectively); Visuospatial/Constructional performance showed a modest but statistically significant decline (of 0.80±0.25 points per year). Few variables predicted cognitive performance; however greater psychiatric symptom severity was associated with worse cognitive performance for most cognitive measures. Conclusions Cognitive functioning in middle-aged persons with schizophrenia showed an absence of decline for most measures and modest gains in some measures.