We evaluated the effect of long-cycle structured intermittent therapy (SIT; 4 weeks without highly active antiretroviral therapy [HAART] followed by 8 weeks with HAART) versus continuous HAART. The study was prematurely terminated to new enrollment because of the emergence of genetic mutations associated with resistance to antiretroviral drugs in 5 patients. After 48 weeks, there was no significant difference between groups in lipid, hepatic transaminase, and C-reactive protein levels in 41 patients. Although there were no differences in CD4+ or CD8+ T cell counts or the percentage of cells that were CD4+CD25+, CD8+CD25+, or CD4+DR+, patients who received SIT had a significantly higher percentage of CD8+CD38+ and CD8+DR+ cells. There was no clear autoimmunization effect by immunologic or virologic parameters. There was no benefit to long-cyde SIT versus continuous HAART with regard to certain toxicity, immunologic, or virologic parameters.