Objective: It has been reported that bipolar disorder may become less responsive to previously effective treatment with each symptomatic relapse. The primary goal of this study was to assess the rate of restabilization after the resumption of lithium ([Li[superscript +]) plus divalproex (DVPX) following relapse on either agent as monotherapy. Method: This is a prospective, 8-week, open-label outpatient [Li[superscript +]/DVPX combination therapy trial. Patients ages 5 to 17 years with bipolar disorder type I or II, who had achieved symptom remission with [Li[superscript +]/DVPX combination therapy and subsequently relapsed during treatment with [Li[superscript +] or DVPX monotherapy were enrolled between January 1999 and January 2003 Results: Thirty-eight patients with a mean age of 10.5 years entered the study. Thirty-four (89.5%) patients responded to treatment with [Li[superscript +]/DVPX mood stabilizer therapy alone, but four patients required adjunctive antipsychotic treatment to address residual symptomatology. Overall, reinitiation of [Li[superscript +]/DVPX combination therapy was well tolerated with no subjects discontinuing because of a medication-related adverse event. Conclusions: It appears that most youths with bipolar disorder who stabilize on combination [Li[superscript +]/DVPX therapy and subsequently relapse during monotherapy can safely and effectively be restabilized with the reinitiation of [Li[superscript +]/DVPX combination treatment. (Contains 2 figures and 4 tables.)