<b><i>Background:</i></b> Smokers with and without chronic obstructive pulmonary disease (COPD) are at risk of severe outcomes like exacerbations, cancer, respiratory failure, and decreased survival. The mechanisms for these outcomes are unclear; however, there is evidence that blood lymphocytes (BL) number might play a role. <b><i>Objective:</i></b> The objective of this study is to investigate the relationship between BL and their possible decline over time with long-term outcomes in smokers with and without COPD. <b><i>Methods:</i></b> In 511 smokers, 302 with COPD (COPD) and 209 without COPD (noCOPD), followed long term, we investigated whether BL number and BL decline over time might be associated with long-term outcomes. Smokers were divided according to BL number in high-BL (≥1,800 cells/µL) and low-BL (&#x3c;1,800 cells/µL). Clinical features, cancer incidence, and mortality were recorded during follow-up. BL count in multiple samples and BL decline over time were calculated and related to outcomes. <b><i>Results:</i></b> BL count was lower in COPD (1,880 cells/µL) than noCOPD (2,300 cells/µL; <i>p</i> &#x3c; 0.001). 43% of COPD and 23% of noCOPD had low-BL count (<i>p</i> &#x3c; 0.001). BL decline over time was higher in COPD than noCOPD (<i>p</i> = 0.040). 22.5% of the whole cohort developed cancer which incidence was higher in low-BL subjects and in BL decliners than high-BL (31 vs. 18%; <i>p</i> = 0.001) and no decliners (32 vs. 19%; <i>p</i> = 0.002). 26% in the cohort died during follow-up. Furthermore, low-BL count, BL decline, and age were independent risk factors for mortality by Cox regression analysis. <b><i>Conclusion:</i></b> BL count and BL decline are related to worse outcomes in smokers with and without COPD, which suggests that BL count and decline might play a mechanistic role in outcomes deterioration. Insights into mechanisms inducing the fall in BL count could improve the understanding of COPD pathogenesis and point toward new therapeutic measures.