In 2014, panel physicians from the International Organization for Migration (IOM), who conduct Department of State-required predeparture examinations for U.S.-bound refugees at resettlement sites in Uganda, noticed an unusually high number of Congolese refugees with enlarged spleens, or splenomegaly. Many conditions can cause splenomegaly, such as various infections, liver disease, and cancer. Splenomegaly can result in hematologic disturbances and abdominal pain and can increase the risk for splenic rupture from blunt trauma, resulting in life-threatening internal bleeding. On CDC's advice, panel physicians implemented an enhanced surveillance and treatment protocol that included screening for malaria (through thick and thin smears and rapid diagnostic testing), schistosomiasis, and several other conditions; treatment of any condition identified as potentially associated with splenomegaly; and empiric treatment for the most likely etiologies, including malaria and schistosomiasis. CDC recommended further treatment for malaria with primaquine after arrival, after glucose-6-phosphate dehydrogenase testing, to target liver-stage parasites. Despite this recommended treatment protocol, 35 of 64 patients with available follow-up records had splenomegaly that persisted beyond 6 months after resettlement. Among 85 patients who were diagnosed with splenomegaly through abdominal palpation or ultrasound at any point after resettlement, 53 had some hematologic abnormality (leukopenia, anemia, or thrombocytopenia), 16 had evidence of current or recent malaria infection, and eight had evidence of schistosomiasis. Even though primaquine was provided to a minority of patients in this cohort, it should be provided to all eligible patients with persistent splenomegaly, and repeated antischistosomal therapy should be provided to patients with evidence of current or recent schistosomiasis. Given substantial evidence of familial clustering of cases, family members of patients with known splenomegaly should be proactively screened for this condition.