<h3>Introduction</h3> Rotavirus is the most common cause of severe infectious gastroenteritis in infants. The live vaccine, while effective in immunocompetent patients, has been associated with life-threatening infection in infants with Severe Combined Immunodeficiency (SCID). We present a case of lymphopenia and hypogammaglobulinemia following rotavirus vaccination in a previously immunocompetent patient. <h3>Case Description</h3> A 3-month-old, ex-full-term Latinx female, presented with worsening diarrhea beginning one-week post rotavirus vaccination. She was meeting age-appropriate milestones, had a negative newborn screen (NBS), including SCID screen, and no pertinent family history. She was admitted for un-resolving diarrhea, electrolyte abnormalities, lymphopenia and hypogammaglobulinemia. Stool rotavirus PCR was positive 8 weeks after vaccination. Total IgG and IgM were low. The presence of a thymus was confirmed on ultrasound. EGD and flexible sigmoidoscopy were grossly normal. She received palivizumab, IVIG, and bactrim and fluconazole prophylaxis. Diarrhea resolved one week after hospitalization. Repeat NBS at 4 months of age demonstrated TRECs of 28/ul. Absolute CD45RA and CD45RO were low. ADA and PNP enzyme, whole exome genome sequencing, chromosomal microarray, and plasma amino acid profile were normal. At 8 months of age, she had mild B-cell lymphopenia with decreased absolute counts and normal percentage. Her leukopenia, neutropenia, and T-cell lymphopenia resolved. <h3>Discussion</h3> The temporal relationship of vaccine administration with onset of clinical findings, the persistently positive stool rotavirus PCR, and the absence of other clear etiology suggests rotavirus vaccine as the inciting factor for this patient's presentation. This case highlights a potentially rare subset of immunocompetent patients who could contract rotavirus infection from the rotavirus vaccine.