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Background Postmenopausal sexual function presupposes the integration of hormonal, neural, and vascular interactions and is subject to optimal crosstalk among psychological, interpersonal, cultural, and environmental factors. Sense of coherence (SOC) reflects a person's ability to cope with stressors and may influence the occurrence of menopausal symptoms and sexual dysfunction. Aim To investigate the association of severity of climacteric symptoms, cardiometabolic risk factors, and SOC with sexual function in postmenopausal women. Methods Overall 281 sexually active postmenopausal women without significant psychopathology or cardiovascular disease attending the Menopause Unit of Aretaieion Hospital were evaluated by the Female Sexual Function Index (FSFI), Greene Climacteric Scale, Beck Depression Scale, and Sense of Coherence Scale. Hormonal and biochemical parameters and cardiometabolic risk factors were evaluated. FSFI scores <26.5 were considered pathologic. Outcomes Total and subdomain scores of sexual response were determined. Results Pathologic FSFI scores were found in 79.7% of the sample. Linear models of multivariable regression analysis showed that FSFI scores were associated with (1) Beck scores (b  = −0.200; 95% CI, −0.472 to −0.073, P  = .001), vasomotor symptom severity (b  = −0.324; 95% CI, −0.985 to 0.051; P <.001), and age and (2) SOC (b  = 0.150, 95% CI, 0.036-0.331; P  = .008), vasomotor symptom severity (b  = −0.361; 95% CI, −0.743 to 0.245; P <.001), and age. Both models were adjusted for menopausal age, diabetes mellitus, hypertension, type of menopause, and menopausal hormone therapy intake. SOC was associated with Beck depression scores (β = −0.487, P <.001; Greene Climacteric Scale total scores, β = −0.199, P <.001). FSFI score <26.5 vs >26.5 was associated with SOC (odds ratio, 0.982; 95% CI, 0.563 to 1.947; P  = .006) and moderate to severe vasomotor symptom severity (odds ratio, 2.476; 95% CI, 1.478 to 3.120; P  = .009) independent of age, diabetes mellitus, hypertension, menopausal hormone therapy intake, type of menopause, or Beck depression classification. Clinical Implications The results indicate the importance of psychometric assessment of postmenopausal women when presenting with scores of low sexual function. The severity of vasomotor symptoms should also be addressed in any case. Strengths and Limitations This is the first study investigating the relationship between SOC and sexuality in menopause in a carefully selected homogenous population. Limitations included the cross-sectional design and the fact that sexual distress was not assessed. Conclusions Pathologic FSFI scores were highly prevalent in this sample of postmenopausal women. FSFI is associated positively with age and severity of vasomotor symptoms and negatively with SOC. [ABSTRACT FROM AUTHOR]