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Mothers of children with serious illnesses have lower levels of well-being than mothers in the general population. Problem-solving therapy (PST), a cognitive-behavioral intervention, has been shown to be effective in treating negative affectivity (depression, anxiety) and other manifestations of reduced well-being. This report describes a problem-solving skills training (PSST) intervention, based on problem-solving therapy, for mothers of newly diagnosed pediatric cancer patients. Ninety-two mothers were randomly assigned to receive PSST or to receive standard psychosocial care (Control Group). After the 8-week intervention, mothers in the PSST Group had significantly enhanced problem-solving skills and significantly decreased negative affectivity compared with controls. Analysis revealed that changes in self-reports of problem-solving behaviors accounted for 40% of the difference in mood scores between the two groups. Interestingly, PSST had the greatest impact on improving constructive problem solving, whereas improvement in mood was most influenced by decreases in dysfunctional problem solving. The implications of these findings for refinement of the PSST intervention and for extension to other groups of children with serious illnesses are discussed.