Purpose: Dose prediction accuracy of dose calculation algorithms is important in external beam radiation therapy. This study investigated the effect of air gaps on depth dose calculations computed by collapsed cone convolution superposition (CCCS) algorithm. Methods : A computed tomography (CT) scan of inhomogenous phantom (30 × 30 × 30 cm 3 ) containing rectangular solid-water blocks and two 5 cm air gaps was used for central axis dose calculations computed by CCCS in Pinnacle treatment planning system. Depth dose measurements were taken using a cylindrical ionization chamber for identical beam parameters and monitor units as in the depth dose computations. The calculated and the measured percent depth dose (PDDs) were then compared. The data presented in this study included 6 MV photon beam and field sizes of 3 × 3 cm 2 , 5 × 5 cm 2 , 10 × 10 cm 2 , and 15 × 15 cm 2 . Results: The results of CCCS were within ±1.4% in the first water medium. However, upon traversing the first air gap and re-entering the water medium, in comparison to the measurements, the CCCS under-predicted the dose, with difference ranged from -1.6% to -3.3% for 3 × 3 cm 2 , from -2.4% to -4.2% for 5 × 5 cm 2 , from -2.4% to -6.7% for 10 × 10 cm 2 , and from -1.6% to -6.3% for 15 × 15 cm 2 . After the second air gap, the CCCS continued to under-predict the dose, and the difference ranged from -3.2% to -3.9% for 3× 3cm 2 , from -2.4% to -5.6% for 5 × 5 cm 2 , from -2.3% to -6.0% for 10 × 10 cm 2 , and from -1.5% to -5.6% for 15 × 15 cm 2 . Conclusion : The CCCS under-predicted the dose in water medium after the photon beam traversed the air gap. Special attention must be given during the patient set-up since large air gap between the patient body and immobilization devices may lead to unacceptable dose prediction errors. ---------------------------------------------- Cite this article as: Oyewale S. Dose prediction accuracy of collapsed cone convolution superposition algorithm in a multi-layer inhomogenous phantom. Int J Cancer Ther Oncol 2013; 1 (1):01016. DOI: http://dx.doi.org/10.14319/ijcto.0101.6