This study aimed to test whether a correlation exists between single-dose resistance to zeocin and the ability to develop a zeocin-induced adaptive response (AR) in Chlamydomonas reinhardtii strains. Three genotypes were used: wild type (WT) strain 137C and two strains (H-3 and AK-9-9), which are highly resistant to radiation based on survival studies. Based on a micro-colony assay, the strains could be arranged according to their single-dose resistance to zeocin as follows: AK-9-9 > H-3 > 137C. However, zeocin induced a similar level of DSB in strains AK-9-9, H-3 and 137C. The radio- and zeocin-resistant strains AK-9-9 and H-3 showed higher DSB rejoining capacity than the WT strain 137C, suggesting that DSB rejoining can at least partly account for different cell survival. Both WT and radio-resistant strains develop zeocin-induced AR involving increased DSB rejoining. The radio- and zeocin-resistant strains AK-9-9 and H-3 again showed higher DSB rejoining capacity than the WT strain 137C. The higher resistance of strains H-3 and AK-9-9 did not abrogate their ability to adapt, albeit with a smaller magnitude as compared to the WT strain. The obtained results characterize new radio-resistant C. reinhardtii strains, which enrich the collection of resistant C. reinhardtii strains.