Chronic obstructive pulmonary disease (COPD) has been identified as an enormous growing worldwide health problem associated with long-term exposure to toxic gases and particles, most often related to cigarette smoking, heavily challenging our current millennium. The present article briefly reviews the evidence of the causes of death in COPD, while focusing on the impact of two of their most common and characteristic systemic effects, also named comorbidities-namely, lung cancer and cardiovascular disease-and drawing the attention to a new field of growing interest, namely the metabolic syndrome, and its potential interplay with the natural course of COPD. A comorbidity is defined as one or more distinct disorders (or diseases) in addition to COPD, regardless of whether this condition is or is not directly related to COPD, and irrespective of whether it is or is not part of the spectrum of the natural history of COPD.