Meconium obstruction of prematurity is a distinct clinical condition that occurs in very low birth weight infants, predisposing them to intestinal perforation and a prolonged hospitalization if not diagnosed and treated promptly. We report a series of 21 infants, including 2 detailed case reports, whose clinical course is indicative of meconium obstruction of prematurity. Specific risk factors are identified along with descriptions of clinical and radiologic findings, disease course, treatment, and outcome. Meconium obstruction of prematurity was more common in infants with a maternal history of pregnancy-induced or chronic hypertension, suggesting the possibility of decreased intestinal perfusion prenatally. Inspissated meconium was located most frequently in the distal ileum, making this disease process difficult to treat. Gastrografin enemas were safe, diagnostic, and therapeutic. Delay in diagnosis and treatment was associated with perforation and delay in institution of enteral feeds.