The efficacy of calixarenes for the storage and/or detection of small guest molecules at the upper-rim is well-known. As part of our continuing efforts to investigate the ability to fine-tune the structure and hence host–guest binding characteristics of calixarenes, we present a systematic investigation of the effect of methylation of the lower-rim tetraphenolic pocket of calixarene (C) on binding at the upper-rim for a test-suite of guest molecules consisting of H2, O2, N2, H2O, CO2, NH3, H2S, N2O, HCN, and SO2. Results of the effects on the host–guest binding for all permutations of single, double, triple and quadruple methylations are presented. It was found that while a tetraphenolic C host does not discriminate between many of the guest molecules in terms of binding energies, progressively methylated lower-rim C hosts introduce differences in guest binding energies within the upper cavity to the extent where it may be possible to competitively bind one guest over another over a wide range of guests. In this regard, this family of methylated C hosts show promise as gas separation devices.