Mental retardation (MR) remains one of the most lifelong handicaps. Chromosomal abnormalities are important cause of MR and they are usually combined with congenital anomalies. Catechol-O-methyltransferase (COMT) plays an important role in breakdown of dopamine in the prefrontal cortex and this is functionally related to individual intellectual ability. Two co-dominant alleles (G and A) in exon 4 of the COMT gene influence the amino acid structure (Val or Met) at codon 158. Therefore, the COMT enzyme activity is genetically polymorphic with trimodal distribution (high activity in Val/Val genotype, intermediate activity in Val/Met genotype, and low activity in Met/Met genotypes). The current study was conducted on 40 mentally retarded patients with stigmata of dysmorphology and malformations to detect chromosomal abnormalities and to clarify the association between COMT gene polymorphism and intelligence quotient (IQ) level. They were classified into two groups. Group I: 26 patients (65%) with mild and moderate degree of MR (IQ: 35-70) and Group II: 14 patients (35%) with severe degree of MR (IQ: 20-34). All patients were subjected to full clinical examination, karyotyping by conventional GTG banding and assay of genetic polymorphism of catechol-O-methyltransferase by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Association of MR with congenital anomalies was present in 70% of studied patients, 2.5% had major anomalies in the form of ventricular septal defect and minor anomalies were detected in 67.5% in the form of: eye abnormalities in 67%, mouth abnormalities in 60%, ear abnormalities in 55%, nose abnormalities in 52.5%, hand and skeletal abnormalities in 12.5%, speech delay in 20% and urogenital manifestations in 5% of the studied patients.47.5% of the studied patients had more than three minor anomalies in the craniofacial region. The results of karyotyping by conventional GTG banding revealed that 87.5% of the studied patients had normal karyotype and 12.5% had chromosomal abnormalities. Numerical chromosomal abnormalities were detected in 5% [(47,XY, +Marker in 2.5% and 47,XX,+Marker in 2.5%)], structural chromosomal abnormalities in 5% [(46,XX,del(9)(p22p24) in 2.5% and 46,XY,dup(22)(p11) in 2.5%] and sex chromosomal abnormalities in 2.5% ((46,XY,del(Y)(p11)). The frequency of wild COMT (HH) genotype (55%) was the highest followed by heterozygous mutant (HL) genotype (37.5%) and homozygous mutant (LL) genotype (7.5%) i.e. the mutant COMT genotypes (HL,LL) were detected in 45% of the studied patients. The results of COMT genotyping by PCR-RFLP revealed that significantly higher mean IQ score in patients with wild (HH) genotype (42.1 ± 8.9) compared to those with mutant (HL, LL) genotypes (36.2 ± 11.8) p-value = 0.14. It could be suggested that the association between COMT gene polymorphism and IQ level in MR is present, as the mutant COMT (HL, LL) genotypes showed an increased risk in reduction of IQ level. Odds ratio (OR) for IQ groups is 5.625, 95% confidence interval = 1.349-23.449. The results of this study need to be confirmed by subsequent studies investigating a larger number of patients in each group to avoid statistical interference and bias. More trials are needed to clearly delineate the magnitude of the role of COMT gene polymorphism in the pathogenesis of MR that might lead towards realistic therapies or preventive strategies for it.