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Backgrounds: Despite the significant global health impact of cardiometabolic multimorbidity (CMM), our understanding of potential predictors associated with its development in smokers, remains limited. Objective: This study aimed to investigate whether a new COPD diagnosis and the rate of lung function decline serve as predictors for incident CMM (defined as having at least two of the following comorbidities: cerebro-cardiovascular diseases, hypertension, dyslipidemia, and diabetes mellitus) in smokers. Methods: An observational longitudinal analysis of prospectively collected data was conducted, including smokers without a previous COPD diagnosis and any cardiometabolic conditions. Sociodemographic and clinical data (body mass index, smoking history, respiratory symptoms, and hospital admissions) were collected at baseline. Lung function tests were performed at baseline and at the end of the follow-up period. The incidence of CMM, a new positive diagnosis of COPD, and the forced expiratory volume in 1 s (FEV1) annual rate of decline were prospectively registered. Adjusted Cox proportional hazard models were adopted to explore risk factors associated with the incidence of CMM. Results: From the 391 smokers included in the study, 207 (53%) were newly diagnosed with COPD, and 184 had a preserved spirometry at baseline (non-COPD group). After nearly a decade of follow-up, 34% (n = 133) of smokers developed CMM. This group was characterized by male predominance, older age, higher BMI and pack-years of smoking, lower post-FEV1, baseline COPD diagnosis, and a history of hospital admission. A positive diagnosis of COPD at baseline and a greater rate of lung function decline (ΔFEV1 ≥ 40 mL/year) were independent predictors for developing CMM. Conclusions: A new COPD diagnosis and an accelerated decline in lung function are significantly associated with the development of CMM in smokers. [ABSTRACT FROM AUTHOR]