<title>Abstract</title> <bold>Purpose</bold>: <italic>Streptococcus pneumoniae (Spn</italic>) is the primary bacterial cause of lower respiratory tract infections (LRTI) globally, particularly impacting older adults and children. While <italic>Spn</italic> colonization in children is linked to LRTI, its prevalence and consequences in adults with comorbidities remains uncertain. This study aims to provide novel data in that regard. <bold>Methods</bold>: This is a prospective study of outpatient adults with chronic diseases. Data on demographics, vaccination, and clinical history was gathered. Nasopharyngeal aspirate samples were examined for Spn colonization using traditional cultures and PCR. Patients were followed for 18 months, with colonization prevalence calculated and factors influencing colonization and its impact on clinical outcomes analyzed through logistic regressions. <bold>Results</bold>: 810 patients were enrolled, with 10.1% (82/810) identified as colonized. The mean (SD) age was 62 years (±15), and 48.6% (394/810) were female. Major comorbidities included hypertension (52.2% [423/810]), cardiac conditions (31.1% [252/810]), and chronic kidney disease (17.4% [141/810]). Among all, 31.6% (256/810) received the influenza vaccine in the previous year, and 10.7% (87/810) received anti-<italic>Spn</italic> vaccines. Chronic kidney disease (OR 95% CI; 2.48 [1.01-6.15], p=0.04) and chronic cardiac diseases (OR 95% CI; 1.62 [0.99-2.66], p=0.05) were independently associated with Spn colonization. However, colonization did not increase the risk of LRTI (OR 95%CI; 0.64 [0.14-2.79], p=0.55) or unfavorable outcomes (OR 95% CI;1.17 [0.14-2.79], p=0.54) during follow-up. <bold>Conclusions</bold>: Chronic kidney and cardiac diseases are independently associated with <italic>Spn</italic> colonization, underscoring the importance of vaccination in this population. <italic>Spn </italic>colonization was not associated with LRTI/unfavorable outcomes in adult patients with chronic comorbidities.