Background: Diarrhea is still appeared to be as one of the leading global killers and disability-adjusted life-years lost, particularly in the infant and children. As per WHO, about 88% of diarrhea-related deaths are attributable to unsafe water, inadequate sanitation and insufficient hygiene, mainly in developing world. Thus, the main objective of this study was to find out the risk of such factors that contribute for diarrhea-related infant mortality in Eastern Ethiopia. Methods: This study employed community based unmatched nested case-control study design in Eastern Ethiopia. The cases were infants who died from diarrheal disease while controls were those who survived their first year of life from September, 2016 to August, 2018. A total of 305 study subjects (61 cases and 244 controls) were included in the study. Infants dying from diarrhea were compared to four neighborhood controls in terms of several risk components of Water, Sanitation and Hygiene. Data were collected from mothers/care takers of infants using pre-tested structured questionnaires, and entered onto CSpro version 5.1 and transform to SPSS version 23 to analyzed potential risk factors. Findings: Finding of this study revealed that the risk factors such as age of mother with <20 years old, unsafe drinking water storage, infants in households without point-of-use water treatment practices, households with unimproved sanitation status, unsafe disposing of child faeces and improper management of solid waste found to be significantly less likely to contribute infants dying from diarrhea than those with their reference group. Infants in households with improper management of liquid waste management strongly association which had three times more likely to occur diarrhea-related infant death (AOR: 3.43, 95% CI: 1.34, 8.76). Infants whose mother/caretaker practiced hand washing with less critical time (one-two occasions) had three times greater risk to infant death from diarrhoea than those who had practice more than three critical times of hand washing (AOR: 3.04, 95% CI: 1.13, 8.17). Conclusion: This study suggests that infants in households with improper management of liquid waste and hand washing practices with fewer occasions (one-two critical time) are a greater risk of getting a diarrhea-related infant death. Therefore, efforts should be made to ensure intervention taking such risk factors into consideration, typically in the infantile period. Key words: Diarrhea-related Infant Mortality, Risk factors, Water, Sanitation and Hygiene