We investigated the relationship between the functional insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and the risk of nicotine dependence in Croatian schizophrenia patients. We also tested whether interactions between ACE-I/D polymorphism and smoking status affected the clinical psychopathology findings in patients as measured using Positive and Negative Symptom Scale (PANSS) scores. Polymerase chain reaction analysis was used to genotype 267 chronically ill schizophrenia patients (140 males/127 females). There were no significant differences in the distribution of ACE genotypes and alleles in male or female schizophrenia patients who were stratified based on their smoking status. However, there was a trend toward a difference in the ACE genotype distribution in female smokers vs. nonsmokers (chi(2) = 5.13, p = 0.077) that was due mainly to the significant overrepresentation of ACE-ID heterozygous genotypes in female smokers compared to nonsmokers (62.3 vs. 42.0%, p = 0.025). ACE-ID heterozygous females had about a twofold higher smoking risk than ACE-II and ACE-DD homozygous carriers (OR = 2.29, 95% CI 1.1-4.7, p = 0.026). We observed no contribution of the ACE genotype-smoking interaction to PANSS psychopathology. This is the first study to investigate the possible association between ACE-I/D polymorphism and nicotine dependence in schizophrenia. Our results suggest that the ACE-I/D polymorphism may be relevant in determining the risk of nicotine dependence in female patients with schizophrenia while the ACE genotype-smoking interaction does not contribute to the clinical expression of schizophrenia.