Two trials were conducted to evaluate the effects of ionophore rotation programs on performance and digestion by feedlot cattle. A 90% concentrate diet was fed with treatments of no ionophore (C), 33 mg lasalocid/kg diet daily (L), 29 mg monensin plus 11 mg tylosin/kg diet daily (MT), and daily (D) and weekly (W) rotation of L and MT. In Trial 1, feedlot performance of 200 crossbred steers (average initial BW 296 kg) was evaluated during a 133-d period. In Trial 2, four crossbred steers (average initial BW 376 kg) fitted with ruminal, duodenal and ileal cannulas were used in a 4 x 4 Latin square design to evaluate treatment effects (excluding W) on ruminal fermentation and site and extent of digestion. In Trial 1, daily rotation of L and MT improved (P less than .10) feed:gain ratio compared with other treatment groups, but daily feed intake did not differ (P greater than .10) among treatments. Daily gain was greater (P less than .10) for steers fed D than for those fed C or MT, but not different from that of steers fed L or W. Carcass measurements did not differ (P greater than .10) among treatments. In Trial 2, ruminal molar proportions of butyrate and valerate were decreased (P less than .07) by MT and D compared with C and L. Proportions of other VFA, ammonia concentrations and ruminal pH did not differ among treatments. Ionophore treatments did not affect site or extent of digestion of OM, starch or N; no differences among treatments were observed for efficiency of microbial protein synthesis. Although daily rotation of L and MT improved performance of growing-finishing feedlot steers, this improvement was not attributable to alterations in ruminal fermentation, or in site or extent of nutrient digestion.