Background: Malignancy is a major complication in patients with primary immunodeficiency (PID), yet data regarding its frequency in Iran are scarce. This study aimed to determine the frequency and pattern of malignancies among patients with PID in a single center in northeastern Iran. Methods: A cross-sectional study was conducted on 145 patients with PID registered at Mashhad University of Medical Sciences between 2015 and 2022. Demographic data, type of immunodeficiency, consanguinity, malignancy type, clinical course, chemotherapy, complications, and mortality were analyzed. Results: Of the 145 patients, 8 (5.5%) developed malignancy. Among them, 7 (87.5%) had lymphoma—primarily non-Hodgkin lymphoma—while 1 (12.5%) had a brain tumor. Four patients (50%) had immunoglobulin-related PID. Chemotherapy complications included thrombocytopenia, petechiae, mucosal candidiasis, and systemic symptoms. Parental consanguinity was reported in 7 patients (87.5%). The majority of malignancy cases (62%) occurred in female patients. The mean age of patients with malignancy was 12.87 years. Conclusion: The frequency of malignancy, particularly lymphoma, was high in patients with primary immunodeficiency. A strong association was observed between malignancy and immunoglobulin-related PID, female sex, and parental consanguinity. These findings highlight the importance of early detection, regular screening, and long-term follow-up in PID patients to improve malignancy-related outcomes.