BACKGROUND: Among patients with common variable immunodeficiency (CVID) patients with complications of immune dysregulation (CVIDc) have higher mortality rates compared to those with infection-only presentation (CVIDio). Therefore, identifying predictive markers of premature mortality among CVIDc patients is crucial. OBJECTIVE: The purpose of this retrospective exploratory study was to describe the mortality in a large tertiary referral center and compare the clinical and laboratory characteristics of CVIDc patients who died prematurely with a group of matched living CVIDc control patients to identify potential indicators of premature death. METHODS: The study included patients diagnosed with CVID according to ESID criteria and active follow-up. In a case-control analysis, we identified patients who died before the age of 70 years as cases, and then randomly selected controls who were matched for sex, age, and CVID phenotype. RESULTS: We were able to confirm the poor prognosis of CVIDc compared to CVIDio in 497 patients, including 57 who had died. The most common causes of death were infections and neoplasia. The exploratory case-control analysis of 37 cases and 73 controls suggests that cases had a higher prevalence of severe enteropathy, hepatopathy, and neoplasia when compared with controls three years prior to death. This was associated with a higher frequency of lymphopenia, thrombocytopenia, and liver enzyme elevation. CONCLUSION: Hepatopathy and severe enteropathy need to be confirmed in a multicenter prospective study as the most relevant factors associated with premature mortality in CVIDc patients. Their early evaluation will hopefully allow for better and possibly more definitive treatment options.