Background Globally, health care-associated infections had become serious public health importance. Compliance with standard safety precaution is effective and inexpensive measure to improve quality of healthcare in reducing occurrence of healthcare associated infections. In developing countries, like Ethiopia adherence to recommended standard safety precaution is scanty. Objective To assess level of compliance with standard safety precaution and associated factors among healthcare workers in Hawassa comprehensive specialized hospital Southern Ethiopia. Methods An institutional based cross-sectional study was conducted at Hawassa comprehensive specialized hospital. Data were collected by using self-administered questionnaire. Study participants were allocated proportionally based on their profession by using stratified random sampling method. Data were entered and analyzed by using SPSS version 20.0. Bivariable analysis and multi variable logistic regression model were used to check which variables were associated with dependent variable. P-values � 0.05 were considered statistically significant. In this study the overall compliance with standard safety precaution among healthcare workers were only 56.