Background: Childhood diarrhoea is a leading cause of morbidity and mortality in developing countries, particularly in sub-Saharan Africa including Ethiopia. Poor water handling, unsafe disposal of excreta and unhygienic practices of mothers/caretakers are some of the risk factors for the transmission of childhood diarrhea. Improving knowledge, attitude and household hygiene practices of mothers are potentially the most effective means of reducing the burden of diarrhoeal diseases in children. OBJECTIVE: To assess knowledge, attitude and household hygiene practice of mothers of children aged less than five years related to the occurrence of diarrheal disease among under five children in Awi Zone, West Amhara region. METHODS: Community based cross-sectional study was employed using both quantitative and qualitative research methods from January to February 2010 in 12 rural kebeles of Awi zone, West Amhara region. Kebeles were chosen by random sampling technique. A total of 422 households that had at least one under-five child were selected by random sampling technique from list of census frame. A structured and pre-tested questionnaire was used to collect quantitative data. Four focus group discussions (FGDs) were also held to generate important idea for the study. Data were entered into EPI Info version 6.04 and it was also edited, cleaned, and analyzed using SPSS version 16.0. Odd ratio with 95% CI was employed to test the significant association and multiple logistic regressions were also used to control confounders. RESULTS: The multivariate regression model showed that children in the age category of 12-23 months were 6.5 times more likely to be affected by diarrhea as compared to those children in the age category of 36 – 59 months [AOR: 6.48, 95% CI: (2.23,18.84)]. Use of unprotected water sources, poor utilization of latrine and feces seen around the yard were significant predictors for the occurrence of childhood diarrhea in bivariate analysis (p<0.05). Mothers/caretakers have high knowledge on key critical handwashing times of before preparing food (96.4%) and after eating food (84.6%). Crude association was observed in the practices of hand-washing after defecation, habit of body bath taking by mothers and frequency of washing hands with soap (p<0.05). Multiple logistic regression analyses showed mother /caretakers presenting diarrhea [OR: 15.96, 95% CI: (2.27, 112.33)] and early initiating foods [AOR: 4.03, 95%CI: (1.32, 12.31)] were independent predictor of the occurrence of childhood diarrhea. The study also indicated that the two week period prevalence of childhood diarrhea was 20.6%. CONCLUSION: This study substantiates the occurrence of childhood diarrhea was highly related with mothers’/caretakers’ hygienic and child feeding practices in particular and the environmental health characteristics in general. Therefore emphasis should be given to enhance the awareness of mothers/caretakers about household hygiene and childcare practices. Keywords: knowledge, household Hygiene, critical times of hand washing, household environment and Childhood diarrhea