Heavy water enrichment using an inclined Clusius–Dickel thermal diffusion column with side-stream operation has been investigated theoretically. The mathematical model to determine the separation efficiency and the best inclination angle have been developed. Significant improvement in heavy water enrichment can be obtained relative to a classic, vertical without side-stream, design. The study of the effects of design and operating variables points out the design provides greater improvement for lower feed flow rate and higher top and side product ratios.