Rationale: Temporal fluctuations have been demonstrated in lung function and asthma control, but the effect of controller therapy on these fluctuations is unknown. Objectives: To determine if fluctuations in peak expiratory flow (PEF) are predictive of subsequent treatment failure and may be modified by controller therapy. Methods: We applied detrended fluctuation analysis to once-daily PEF data from 493 participants in the LOCCS (Leukotriene Modifier Corticosteroid or Corticosteroid-Salmeterol) trial of the American Lung Association Airways Clinical Research Centers. We evaluated the coefficient of variation of PEF (CVPEF) and the scaling exponent alpha, reflecting self-similarity of PEF, in relation to treatment failure from the run-in period of open-label inhaled fluticasone, and the treatment periods for subjects randomized to (1) continued twice daily fluticasone (F), (2) once daily fluticasone plus salmeterol (F + S), or (3) once daily oral montelukast (M). Measurements and Main Results: The CVPEF was higher in those with treatment failure in the F and F + S groups in the run-in phase, and all three groups in the treatment phase. alpha was similar between those with and without treatment failure in all three groups during the run-in phase but was higher among those with treatment failure in the F and F + S groups during the treatment phase. Participants in all three groups showed variable patterns of change in alpha leading up to treatment failure. Conclusions: We conclude that increased temporal self-similarity (alpha) of more variable lung function (CVPEF) is associated with treatment failure, but the pattern of change in self-similarity leading up to treatment failure is variable across individuals.