The vast majority of microorganisms live under starvation-associated stress conditions that cause mutagenesis despite the limitation of DNA replication and cell division. In this study, we compared the roles of polymerase zeta (Pol zeta) and non-homologous DNA-end joining (NHEJ) in starvation-associated spontaneous base substitutions and frameshifts, using yeast mutants carrying deletions of REV3 (encoding the catalytic subunit of Pol zeta), YKU80 (encoding a protein involved in the initiation of NHEJ), or both genes. We found that approximately 50% of starvation-associated spontaneous frameshifts and 40% of base substitutions required NHEJ to occur. The role of Pol zeta was only slightly less pronounced, with 30-40% of frameshifts and 35-45% of base substitutions being dependent on Rev3. In comparison with the single mutants, the rev3 yku80 double mutant showed an additive decrease in the level of both base substitutions and frameshifts, indicating that Pol zeta and NHEJ function independently in starvation-associated mutagenesis. Our results also imply that about 30% of starvation-associated base substitutions and frameshifts arise by some unknown mechanism that does not involve Pol zeta or NHEJ.