Objectives: To determine the association between home enteral nutrition (HEN) administration modality and its complications in patients. Methods: This is a prospective multicenter longitudinal study including 15 Spanish hospitals, from April 2015 to March 2017. A 4-month follow-up period was conducted for each patient by home visit. The study subjects were adult patients who began their nutrient intake by tube feeding, known as HEN, during the recruitment period. The variables studied included the type and modality of HEN administration and its related complications, such as vomiting, regurgitation, constipation, diarrhea, and abdominal distention. Mechanical complications and bronchoaspiration were also evaluated. Descriptive variables were used for fitting. Results: The study consisted of 306 patients; 4 were lost due to death. Specific HEN modalities protected against constipation (odds ratio (OR) = 0.4) and regurgitation (OR = 0.4). The use of a nasogastric tube (NGT) resulted in a lower risk of diarrhea compared to percutaneous endoscopic gastrostomy (PEG) (OR = 0.4) but resulted in a higher risk of tube obstruction (OR = 7.4). The use of intermittent gravity versus bolus feeding was a protection factor against vomiting (OR = 0.4), regurgitation (OR = 0.3), constipation (OR = 0.3), diarrhea (OR = 0.4) and abdominal distension (OR = 0.4). The increase in the number of doses was a risk factor for the incidence of regurgitation (OR = 1.3). Conclusions: Gastrointestinal complications were the most frequent problems, but an adequate choice of the formula, route, feeding modality, number of doses, administration time, and dose volume can reduce the risk of these complications.