Parental physical illness has been associated with a variety of negative child outcomes but the mechanisms explaining this relationship are not fully understood. Additionally, few studies have explored what role, if any, marital status may play in this relationship. This study used prospective longitudinal survey data from 382 two-parent and 182 single-parent families in the Iowa Youth and Families and Single Parents Project to explore the relationship between maternal illness and parenting with depressed affect as a potential mediator. Multiple group structural equation modeling was used to investigate whether the relationships between these indicators were the same for single and married mothers. Analyses revealed associations between mothers' illness and parenting for both single and married mothers, but mothers' depressed affect played a meditational role for single mothers, which was not evident with married mothers. Both the empirical and clinical implications of these findings are discussed.