We report the first implementation of an advanced waveguide structure, consisting of GaSb separate confinement layers, n-doped InAs/AlSb superlattice intermediate cladding layers, and n þ -doped InAs 0.91 Sb 0.09 plasmon-enhanced cladding layers for GaSb-based interband cascade lasers (ICLs) with lasing wavelengths in the 3 to 4 μm wavelength region. This advanced waveguide configuration for ICLs can have improved thermal dissipation and enhanced optical confinement. Although the grown ICL wafers had significant layer thickness deviations from the designed values, devices made from them exhibited room temperature (RT) threshold current densities as low as 148 A∕cm 2 and high voltage efficiencies (e.g., 69%), implying a considerable potential of the advanced waveguide configuration for further improved device performance. A comparative study among the devices revealed how the structural variations could affect the carrier transport and threshold voltage, providing useful guidance for future research. Additionally, the ICLs tested here had characteristic temperatures of nearly 60 K, which are the highest among RT ICLs with similar lasing wavelengths, supporting the further development of the advanced waveguide in GaSb-based ICLs operating in this wavelength range.