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Background: Gene–environment interactions play a major role in the phenotypic expression of complex disease traits such as those for cardiovascular diseases. Aims: This study aimed to determine the gene–environment interactions that underpin the relationship between interleukin‑10 (IL‑10) single‑nucleotide polymorphism (1082 G/A[rs1800896]) with lifestyle on cardiovascular disease risk in adult Nigerians with type 2 diabetes mellitus(DM). Setting and Design: This case–control study involved patients with type 2 DM with high cardiovascular risk, determined by the Framingham’s classification, and age, sex, and diabetes‑duration matched subjects with low and intermediate cardiovascular risks. Subjects and Methods: The genotypes were detected by polymerase chain reaction (PCR) followed by allelic discrimination using the Applied Biosystems 7900HT Fast Real‑Time PCR System. One‑way analysis of variance and logistic regression were employed for analysis. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated to estimate the risk caused by the polymorphism. P <0.05 was considered significant. Results: The odds for cardiovascular risk decreased progressively in individuals with the GG, GA, and AA genotypes (OR = 0.80, 95% CI = 0.49–1.28, P = 0.345 and OR = 0.46, 95% CI = 0.24–0.88, P = 0.018 for GA and AA genotypes, respectively. A significantly higher proportion of homozygous (AA) individuals were in the low cardiovascular risk group (54.2%, P = 0.018). Compared with the whole study population, individuals with the AA genotype had consistently lower odds for cardiovascular risk in subpopulations like alcohol users (OR = 0.25 [0.11–0.55], P = 0.001), but the odds were higher among smokers (OR = 1.80 [1.14–2.90], P = 0.017) and those with sedentary lifestyles (OR = 2.46, 95% CI = 1.14–5.33, P = 0.024). Conclusions: The homozygous mutant genotype AA of the IL‑10 gene 1082 G/A had a protective effect on cardiovascular risk in type 2 DM. However, this protection was absent in those leading a sedentary lifestyle. [ABSTRACT FROM AUTHOR]