Efavirenz widely prescribed anti-retroviral drug belongs to class II BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility and it requires enhancement in solubility and dissolution rate for increasing its oral bioavailability. The objective of the present investigation is to enhance the solubility, dissolution rate and bioavailability of efavirenz by the use of cyclodextrins (%CD and HP%CD) and surfactant, Solutol HS15. The individual main effects and combined (interaction) effects of cyclodextrins (%CD and HP%CD) and surfactant Solutol HS15 on the solubility and dissolution rate of efavirenz were evaluated in a series of 22 factorial experiments. The solubility of efavirenz in the fluids containing %CD, HP%CD and Solutol HS15 as per 22 factorial design was determined. Efavirenz-CD-surfactant complex systems were prepared employing selected combinations of CDs and surfactant in each case as per a 22 factorial design by kneading method and were evaluated. Pharmacokinetic evaluation was done on efavirenz– %CD (1:2) and efavirenz- %CD-Solutol HS15 (1:2:0.05) complexes in comparison to pure drug with a view to evaluate their in vivo performance in healthy rabbits. The results of the present investigation clearly indicated that the individual main effects as well as combined effects of CDs ( %CD and HP%CD ) and surfactant Solutol HS15 in enhancing the solubility and dissolution rate ( K1 ) of efavirenz are highly significant ( P < 0.01 ). Combination of Solutol HS15 with CDs ( %CD and HP%CD ) resulted in a much higher enhancement in the solubility and dissolution rate ( K1 ) of efavirenz than is possible with CDs and Solutol HS15 alone. %CD-Solutol HS15 combination gave 54.43 fold increase in the solubility and 5.95 fold increase in the dissolution rate (K1) of efavirenz. In the in vivo pharmacokinetic evaluation, %CD has markedly enhanced both the rate (Ka) and extent (AUC) of absorption (i.e. bioavailability) of efavirenz. Addition of Solutol HS15 has further enhanced both the rate of absorption and extent of absorption of efavirenz from efavirenz – %CD- Solutol HS15 (1:2:0.05) complex. Efavirenz-%CD-Solutol HS15 inclusion complex exhibited a 4.92 fold increase in the absorption rate (Ka) and 1.85 fold increase in the (AUC)0 when compared to efavirenz pure drug. Hence a combination of cyclodextrins (%CD and HP%CD) and Solutol HS15 is recommended for enhancing the solubility, dissolution rate and bioavailability of efavirenz, a BCS Class II drug.