The effect of soil microstructure on the compressibility of natural Singapore marine clay is studied in this paper. It was found that natural Singapore marine clay can sustain higher void ratio than reconstituted Singapore marine clay at the same effective stress in one-dimensional compression. This difference is most noticeable between yield stress and two times the yield stress. This void ratio difference is commonly attributed to soil microstructure, and the decrease in this difference at higher stresses is attributed to progressive destructuration. As a consequence of progressive destructuration, the virgin compression curve is nonlinear and the compression index along the virgin compression range is variable, which is only noticeable during the constant rate of strain consolidation test on high-quality samples. In the absence of high-quality samples and constant rate of strain consolidation tests, an empirical method is proposed to obtain a first-order estimation of a nonlinear virgin compression curve using index properties and yield stress. This paper demonstrates that the proposed method works reasonably well with natural Singapore marine clay. The error bound for the predicted compression indices is approximately ±20% of the compression indices measured with constant rate of strain test on high-quality samples.