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Simple Summary: By analyzing inflammatory scores (INFLA-score, Systemic Inflammation Response Index—SIRI) and the Aging-Related Immune Phenotype (ARIP) in 249 participants aged 19–111 years, this study investigates the role of immune-inflammatory responses in semi- and supercentenarians who have survived significant challenges like pandemics. Statistical analyses indicated that the INFLA-score and SIRI increase with age, but no significant differences were observed between semi- and supercentenarians and other age groups. Moreover, ARIP values, specifically CD8 Naïve/Effector scores, calculated from a subcohort of 54 individuals, showed no notable differences across groups. These findings suggest that effective management of immune-inflammatory responses may play a role in achieving extreme longevity. Studying models of healthy aging and exceptional longevity is crucial to understanding a possible longevity signature, as most show resistance to age-related diseases. In particular, semi- and supercentenarians are a highly selected group, having survived significant adversities, including the Spanish flu and COVID-19 pandemics, indicating distinctive immune system characteristics. This paper analyzes the inflammatory scores (INFLA-score, Systemic Inflammation Response Index (SIRI)) and Aging-Related Immune Phenotype (ARIP) indicators calculated from the dataset of the DESIGN project, including 249 participants aged 19–111 years, aiming to understand the immune-inflammatory (IMFLAM) role in achieving longevity. Statistical analyses, including linear regression and one-way ANOVA, were performed to explore the correlations between these parameters and age. Both INFLA-score and SIRI showed a significant increase with age. However, no statistical differences were found when comparing the values of semi- and supercentenarians to other age groups, which are similar to adults and lower than younger centenarians. Regarding ARIP values, it is noteworthy that when comparing the CD8+ Naïve/Effector scores between groups, no significant differences were observed between the semi- and supercentenarian group and the other groups. These results support the idea that the control of IMFLAM response can promote extreme longevity. [ABSTRACT FROM AUTHOR]