It has recently been highlighted that the release behavior of pellets containing microcystalline cellulose (MCC) as the spheronizing agent may be impaired by the lack of disintegration. Although alternative spheronizing excipients have been proposed, their overall advantages have not thoroughly been assessed. In the present work, the possible use of beta-cyclodextrin (betaCD) was therefore explored for the manufacturing of pellets with a potential for effective disintegration and immediate release of poorly soluble active ingredients. MCC/betaCD powder formulations containing no drug or model drugs with different water solubility, able to form inclusion compounds with the employed cyclodextrin, were pelletized by agglomeration in rotary fluid bed equipment. By applying successive statistical experimental designs, the most critical formulation and operating parameters were identified and optimal manufacturing processes were ultimately set up. High yields of pellets provided with satisfactory physical-technological characteristics were obtained using powder formulations with up to 80% betaCD. Based on dissolution testing results, the suitability of betaCD for the preparation of disintegrating MCC-containing pellets with improved dissolution performance was finally demonstrated.