The hydrophobicity of poorly soluble drugs can delay tablets disintegration. We probed here the influence of different disintegrants on the disintegration of challenging hydrophobic formulations. Tablets containing diluents, hydrogenated vegetable oil and either sodium starch glycolate (SSG), croscarmellose sodium (CCS) or crospovidone (XPVP) were prepared. The disintegration time of tablets was tested immediately and after storage at 40 °C and 75% RH in sealed bags. Results show that storage and compression force had a negative effect on disintegration, particularly with 1% disintegrant. The performance of the three disintegrants was in the following order: CCS (best) > SSG > XPVP. For example, tablets containing 1% CCS, SSG and XPVP, compressed at 20 kN, disintegrated in ≈3, ≈12 and ≈69 min, respectively, after two months storage. Settling volume, liquid uptake and effect of storage on physical properties of the pure disintegrants were also studied and revealed that the reduced performance of XPVP is related to: 1) its rapid, yet short-range expansion upon liquid exposure and 2) its change of behaviour on storage. In conclusion, CCS ensured rapid disintegration at low concentration across various compression forces and storage times. Thus, the use of CCS in hydrophobic tablet formulations is recommended.