Background and Objectives: To evaluate the influence of obstructive sleep apnea (OSA)-related symptoms on prevalent cardiovascular disease (CVD) in a large clinical population of patients. Materials and Methods: A total of 2127 patients (mean age 55 years, 24% women) underwent diagnostic polysomnography and were evaluated using the Epworth sleepiness scale (ESS), the Athens Insomnia Scale (AIS), and the Beck Depression Inventory (BDI). We investigated the predictive value of OSA-associated symptoms for prevalent cardiovascular disease, after adjustment for relevant confounding factors including age, obesity, and co-morbidities. Results: Patients with OSA and CVD were older and had a higher Body Mass Index (BMI); the percentage of obese patients was also higher (83% vs. 70%, p < 0001). They also had greater neck, waist, and hip circumferences and a higher waist-to-hip ratio. Excessive daytime sleepiness (ESS ≥ 10) [odds ratio (95% CI) 1.112 (0.708–1.748), p = 0.64], insomnia symptoms (AIS ≥ 6) [odds ratio (95% CI) 0.748 (0.473–1.184), p = 0.21], frequent awakenings [odds ratio (95% CI) 1.599 (1.019–2.508), p = 0.06], and nocturia [odds ratio (95% CI) 1.359 (0.919–2.009), p = 0.124] were not associated with CVD after adjustment for the previous confounders. On the other hand, depressive symptoms (BDI ≥ 10) independently predicted prevalent CVD [odds ratio (95% CI) 1.476 (1.154–1.887), p = 0.002]. Further analysis in subgroups stratified by age, BMI, and gender demonstrated that depressive symptoms predicted prevalent CVD but only in the subgroup of younger (age group < 60 years), obese (BMI group ≥ 30), and male (OR = 1.959, 95% CI = 1.209–3.175, p = 0.006) OSA patients. Conclusions: OSA patients with CVD were more likely to complain of less typical OSA symptoms and depressive symptoms compared to patients without CVD in this large clinical patient cohort, supportingthecomplexity and heterogeneityof OSA.