(1) Background: Psychological wellbeing correlates with improved physical and psychological health, as this construct plays a fundamental role in disease recovery and health maintenance. Hence, for healthcare professionals, understanding the factors that predict psychological wellbeing is of great interest. Thus, the objective of this study was to determine whether health status and personality traits influence psychological wellbeing. (2) Methods: The total sample (N = 600) consisted of HIV patients, individuals with diabetes, and healthy subjects from the Salamanca Clinical Hospital. The instruments used for data collection included a sociodemographic questionnaire, Ryff's Psychological Wellbeing Scale, and the Spanish version of the Big Five Taxonomy to measure personality. (3) Results: Specific personality traits, such as Emotional Stability, Extraversion, Responsibility, and Integrity were significant predictors of different dimensions of psychological wellbeing. Regarding health status, individuals with diabetes and healthy subjects, compared to HIV+ subjects, were associated with higher levels of psychological wellbeing dimensions. (4) Conclusions: Individual differences in personality traits and the diagnosis of a chronic condition may play a fundamental role in psychological wellbeing. These conclusions are of great interest for developing strategies aimed at individuals with chronic illnesses and specific personality traits associated with poorer psychological wellbeing.