Efficient ¹³C hyperpolarization of ketoisocaproate is demonstrated in natural isotopic abundance and [1-¹³C]enriched forms via SABRE-SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei). Parahydrogen, as the source of nuclear spin order, and ketoisocaproate undergo simultaneous chemical exchange with an Ir-IMes-based hexacoordinate complex in CD₃OD. SABRE-SHEATH enables spontaneous polarization transfer from parahydrogen-derived hydrides to the ¹³C nucleus of transiently bound ketoisocaproate. ¹³C polarization values of up to 18% are achieved at the 1-¹³C site in 1 min in the liquid state at 30 mM substrate concentration. The efficient polarization build-up becomes possible due to favorable relaxation dynamics. Specifically, the exponential build-up time constant (14.3 ± 0.6 s) is substantially lower than the corresponding polarization decay time constant (22.8 ± 1.2 s) at the optimum polarization transfer field (0.4 microtesla) and temperature (10 °C). The experiments with natural abundance ketoisocaproate revealed polarization level on the ¹³C-2 site of less than 1%—i.e., one order of magnitude lower than that of the 1-¹³C site—which is only partially due to more-efficient relaxation dynamics in sub-microtesla fields. We rationalize the overall much lower ¹³C-2 polarization efficiency in part by less favorable catalyst-binding dynamics of the C-2 site. Pilot SABRE experiments at pH 4.0 (acidified sample) versus pH 6.1 (unaltered sodium [1-¹³C]ketoisocaproate) reveal substantial modulation of SABRE-SHEATH processes by pH, warranting future systematic pH titration studies of ketoisocaproate, as well as other structurally similar ketocarboxylate motifs including pyruvate and alpha-ketoglutarate, with the overarching goal of maximizing ¹³C polarization levels in these potent molecular probes. Finally, we also report on the pilot post-mortem use of HP [1-¹³C]ketoisocaproate in a euthanized mouse, demonstrating that SABRE-hyperpolarized ¹³C contrast agents hold promise for future metabolic studies.