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Although of unproven benefit for nonalcoholic steatohepatitis (NASH), thiazolidinediones (TZDs) have emerged as a promising therapy. Little evidence exists, however, regarding sustained effects of TZDs in NASH after drug discontinuation. A recent clinical study suggests that relapse of NASH pathophysiology is inevitable and that lifelong therapy may be needed to maintain histologic response.We reviewed extended follow-up data of NASH patients previously treated with troglitazone to evaluate the influence of weight and physical activity on clinical and histologic parameters related to NASH recurrence.After medical record review, 9 of 10 patients had complete data for follow-up and 5 had an extended follow-up biopsy 3 years or more after discontinuing troglitazone therapy.In contrast to recent work showing relapse of NASH to be nearly universal after discontinuation of TZD therapy, 2 of our patients had 1-stage improvement in fibrosis, normal aminotransferases, and absence of diabetes after median follow-up of 37 months after discontinuation of troglitazone. Both patients had sustained exercise programs and interval body mass index reduction. In contrast, active steatohepatitis, progression of fibrosis, and requirement of antidiabetic medications were seen in patients unable to achieve lifestyle modifications.We conclude that sustained histologic response after short-term TZD therapy for NASH is not invariably lost after medication discontinuation but rather is intimately related to sustained changes in lifestyle, particularly physical activity. Activity and diet in the setting of thiazolidinedione or other drug therapy of NASH is an essential consideration that warrants careful incorporation into future drug trials.