Objectives The efficacy of cognitive remediation interventions in schizophrenia has been demonstrated in several experimental studies. However, the effectiveness of such treatments in the usual setting of care of schizophrenia and a direct comparison of different modalities of interventions have not been systematically analyzed. The aim of the study was to assess the effectiveness of the cognitive subprograms of Integrated Psychological Therapy (IPT-cog) and of a computer-assisted cognitive remediation (CACR) method on symptomatological, neuropsychological and functional outcome measures in schizophrenia. Methods Ninety patients with schizophrenia were assigned to IPT-cog, CACR or usual rehabilitative interventions (REHAB) in a naturalistic setting of care. Clinical, neuropsychological, and functional outcome variables were assessed at baseline and after 24weeks of treatment. Results Both the IPT-cog and CACR groups improved more than the comparison group with respect to all outcome variables. The more responsive cognitive domains were speed of processing and working memory. The effectiveness of the 2 remediation methods on the outcome dimensions considered was comparable. However, IPT-cog, but not CACR, was more effective than REHAB on speed of processing, and the CACR group had better outcome than both the REHAB and the IPT-cog groups when the Health of the Nation Outcome Scale was considered. Few correlations between neurocognitive and functional outcome changes were found. Conclusions The study demonstrates the effectiveness, although nongeneralized, of IPT-cog and CACR in schizophrenia when applied within a psychiatric and psychosocial treatment regimen representative of the usual setting and modality of care, with no evident superiority of any of the methods, and indicates that the changes in functional outcome during treatment are modestly mediated by improvement in specific cognitive domains.