Introduction: Cardiovascular disease (CVD) is the leading cause of mortality and one of the main challenges for health systems worldwide. In this study, we aimed to evaluate the role of socio-demographic, lifestyle, psychological factors, anthropometric measurements, and presence of underlying diseases in CVD progression among a subpopulation of Iranian adults. Methods A total of 235 CVD patients were enrolled. The control group also included healthy and non-symptomatic individuals (n = 8405). Health and lifestyle questionnaires, the Beck’s anxiety inventory (BAI), Beck’s depression inventory (BDI) and the James and Schofield human energy requirements equations were completed for all participants. Anthropometric measurements were also evaluated in all subjects. Results After six years of follow-up, we found that there were significant positive correlations between CVD risk and age, body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), diabetes mellitus (DM) and family history (FH) of CVD in both genders; though, there was a significant negative correlation between physical activity level (PAL) and risk of CVD among men and women. Also hypertension (HTN), metabolic syndrome (MS), depression and anxiety were positively and higher education level was negatively associated with CVD events only in females. While, waist-to-hip ratio (WHR) was an independent predictor of CVD among males. Conclusion There are several modifiable and non-modifiable risk factors that were independently considered as CVD predictors among the MASHAD study population. It is recommended that the lifestyle modifications, development of local risk calculators and gender-related stratified strategies should be prioritized in order to prevent and manage CVD among the Iranian population.