In the present investigation, cyclodextrin complexation process was explored for development of tablet formulation of WHO approved fixed dose combination of lopinavir and ritonavir with reduced tablet size, shorter disintegration time and higher bio-availability in comparison to reference product. In preliminary studies, we found that lopinavir solubility and dissolution rate is poor into the dissolution medium recommended by FDA, whereas ritonavir solubilized fairly into dissolution medium with adequate dissolution rate. Solid-state cyclodextrin complexation technology was used for enhancement of dissolution rate of lopinavir into dissolution medium. Various cyclodextrins were screened by comparison on basis of enhancement of dissolution rate of lopinavir (LPV) and the order was found as gamma cyclodextrin (γ-CD) > hydroxypropyl beta-cyclodextrin (HP-β-CD) > methyl beta-cyclodextrin (M-β-CD) > beta-cyclodextrin (β-CD), with Q 120 values (i.e. percentage of dissolved drug at 120 min.) were 10.1 for the pure LPV and 56.3, 51.3, 30.3 and 10.3 for LPV/γ-CD, LPV/HP-β-CD, LPV/M-β-CD and LPV/β-CD, respectively. Anomalous results were found between stability constant, dissolution rate and saturation solubility. It was found that cyclodextrin having higher stability constant value with LPV, provides higher saturated solubility of LPV in aqueous media but at slow dissolution rate and vice versa. The γ-CD was selected for complexation with lopinavir in the stoichiometric ratio 1:1.5 M of LPV to γ-CD. Various processes such as kneading method, milling technique, sonication, freeze drying and autoclaving were tried, from which kneading method was found to give best dissolution results. The corresponding solid complexes were characterized by differential scanning calorimetric, X-ray powder diffraction and scanning electron microscopy studies. Based on various studies, the complexation phenomenon between LPV and γ-CD was found to follow non-inclusion behavior. Pharmacokinetic studies were carried out in Sprague-Dawley rats using cross over design with a 3 day wash out period. The bioavailability of lopinavir was found to be enhanced significantly using cyclodextrin complex tablet formulation. Graphical Abstract: [Figure not available: see fulltext.] © 2011 Springer Science+Business Media B.V.