Strong ionization of the gas medium has significant effects in the process of medium-order harmonic generation. The combined effect of neutral atom depletion and defocusing of the pump beam due to the intensity-dependent density of free electrons, significantly modifies the conversion characteristics and efficiency. For moderate harmonic orders, the yield is optimized for well-defined values of the pump laser intensity that do not depend on the order or on the focusing geometry, but only on the ionization potential of the gas. In particular focusing conditions, the ionization-induced defocusing can effectively guide the pump beam along channels of optimum intensity, thus enhancing the overall conversion efficiency. We demonstrate that a very simple model is able to reproduce all our experimental results in a surprisingly good way.