Di-tert-butyl (E)-4,4'-stilbenedicarboxylate and tert-butyl 4-vinylbenzoate were copolymerized with maleic anhydride and tert-butyl 4-maleimidobenzoate, individually and respectively. After conversion into polyanions, these four copolymers exhibited activity against four HIV-1 strains: IIIb, BaL, JR-CSF, and 92UG037. For both the IIIb and BaL HIV-1 strains, the lowest IC50 (0.095 and 0.23 μg/mL, respectively) values were obtained with poly(4,4'-stilbenedicarboxylate-alt-maleic acid) (DCSti-alt-MA). For JR-CSF and 92UG037, both tier 2 clinical isolates but different clades, DCSti-alt-MA exhibited the lowest IC50 (0.76 and 0.75 μg/mL, respectively). Although DCSti-alt-MA had the lowest IC50 in μg/mL for each strain, the other copolymers had IC50s less than 2-fold higher. Further, these copolymers achieved high selectivity indices (>100) for these clinical isolates. Polymer rigidity, as measured by the statistical segment length, emerged as a key property when comparing anti-HIV activities with those of other polyanions. A speculative illustration was proposed for possible modes of inhibition.