Among children investigated for maltreatment, those with parents experiencing mental illness or substance abuse are more likely to be placed out-of-home; however, little is known about why these children are at greater risk. Using a sample of 2488 Structured Decision Making® assessments administered in San Francisco county from 2011 to 2015, we identified a profile of safety threats that accounts for why workers are more likely to determine children of parents with mental illness and/or substance abuse unsafe in the home. Eight percent of assessments in our sample involved parents with current mental illness only and 10% had comorbid substance abuse. The odds of an unsafe determination more than doubled among parents with mental illness (OR = 2.52, p < 0.001) and were nearly tenfold higher among parents with comorbid substance abuse (OR = 9.62, p < 0.001). Three safety threats accounted for all of the effect of parental mental illness on safety determination: caretaking impairment due to emotional stability/developmental status/cognitive deficiency (57%), failure to meet a child's immediate needs (30%), and threats of harm (14%). Three safety threats accounted for 55% of the effect of comorbid mental illness and substance abuse on safety determination: failure to meet a child's immediate needs (21%), presence of a drug-exposed infant (21%), and caretaking impairment due to emotional stability/developmental status/cognitive deficiency (14%). Results suggest that sustained linkage to effective mental health services and material resources at the outset of a child welfare case may help to promote faster and more likely reunification, and prevent future maltreatment.