The V3 loop of the HIV-1 Env protein is the primary determinant of viral coreceptor usage, whereas the V1V2 loop region is thought to influence coreceptor binding and participate in shielding of conserved regions of the Env surface glycoprotein, gp120, from antibody responses. V1V2 functional properties are partly mediated by changes in primary amino-acid sequence and patterns of glycosylation. However, much remains to be determined concerning patterns of length polymorphism and variation in N-linked glycosylation of gp120 subregions, and how these patterns might relate to HIV pathogenesis. We examined 5254 HIV-1 gp120 nucleotide sequence fragments and clinical data from 154 individuals. Data included previously unpublished HIV-1 subtype B sequences from the MACS and Seattle PIC cohorts, and publicly available sequences from the Los Alamos National Laboratory Database. Sequences were aligned, translated, manually edited and sorted to identify the V1V2, C2, V3, C3, V4, C4 and V5 subregions. Subregion lengths were calculated, and potential N-linked glycosylation sites counted. In crossectional analyses, loop length variation was examined as a function of time since infection, CD4 count, viral load, and calendar year. In longitudinal analyses, loop lengths were examined as a function of time. V1V2 length and glycosylation increased significantly as a function of time since infection and with increasing calendar year. V1V2 length was then found to decline in late-stage illness. However, the clinical parameters examined accounted for only 30% of the variation seen in V1V2 length, and other Env subregions did not vary significantly with respect to the parameters measured. V4 and V5 lengths vary considerably, but correlated poorly with time since infection, CD4 count, viral load, tissue source and stage of illness. Our observations suggest that HIV adapts to selective pressure within the immunocompetent host by increasing the size of V1V2, either by lengthening of the V1V2 amino-acid chain, and/or by adding carbohydrate moieties at N-linked glycosylation sites. As such, these changes likely affect escape from humoral immune responses. Similarly, V1V2 shortening during late-stage infection may reflect waning host immunity.