AbstractGenetic association studies have yielded extensive but frequently inconclusive data about genetic risk factors for schizophrenia. Clinical and genetic heterogeneity are possible factors explaining the inconsistent findings. The objective of this study was to test the association of commonly incriminated candidate genes with two clinically divergent subgroups, non‐deficit (SZ‐ND) and deficit‐schizophrenia (SZ‐D), and symptom severity, in order to test for replication of previously reported results. A homogeneous sample of 280 schizophrenia patients and 230 healthy controls of Hungarian, Caucasian descent were genotyped for polymorphisms in schizophrenia candidate genes NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A. Patients were divided into the diagnostic subgroups of SZ‐ND and SZ‐D using the Schedule for Deficit Syndrome (SDS), and assessed clinically by the Positive and Negative Symptom Scale (PANSS). SNP8NRG241930 in NRG1 and rs1011313 in DTNBP1 were associated with SZ‐ND (P = 0.04 and 0.03, respectively). Polymorphisms in RGS4, G72/G30, and PIP5K2A were neither associated with SZ‐ND nor with SZ‐D. SNP8NRG241930 showed association with the PANSS cognitive and hostility/excitability factors, rs1011313 with the negative factor and SDS total score, and rs10917670 in RGS4 was associated with the depression factor. Although these results replicate earlier findings about the genetic background of SZ‐ND and SZ‐D only partially, our data seem to confirm previously reported association of NRG1 with schizophrenia without prominent negative symptoms. It was possible to detect associations of small‐to‐medium effect size between the investigated candidate genes and symptom severity. Such studies have the potential to unravel the possible connection between genetic and clinical heterogeneity in schizophrenia. © 2009 Wiley‐Liss, Inc.