Modified nucleotides often hinder and/or decrease the fidelity of DNA polymerases. Tandem lesions, which are comprised of DNA modifications at two contiguous nucleotide positions, can be even more detrimental to genome stability. Recently, tandem lesions containing 5-formyl-2’-deoxyuridine (5fdU) flanked at the 5’-position by 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-OxodGuo) or N-(2-deoxy-α,β-D-erythropentofuranosyl)-N-(2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy•dG) were discovered. We examined the replication of 5’− 8-OxodGuo-5fdU and 5’-Fapy•dG-5fdU tandem lesions in HEK 293T cells and several polymerase deficient variants by transfecting single-stranded vectors containing them. The local sequence of the tandem lesions encompasses the 273 codon of the p53 gene, a mutational hot-spot. The bypass efficiency and mutation spectra of the tandem lesions were compared to those of the isolated lesions. Replication of weakly mutagenic 5-fdU is little changed when part of the 5’− 8-OxodGuo-5fdU tandem lesion. G → T transversions attributable to 8-OxodGuo increase > 10-fold when the tandem lesion is bypassed. 5’-Fapy•dG-5fdU has a synergistic effect on the error-prone bypass of both lesions. The mutation frequency (MF) of 5’-Fapy•dG-5fdU increases 3-fold compared to isolated Fapy•dG. In addition, a 5’-adjacent Fapy•dG significantly increases the MF of 5fdU. The major mutation, G → T transversions, decrease by almost a third in hPol κ- cells, which is the opposite effect when isolated Fapy•dG in the same sequence context is replicated in HEK 293T cells in the same sequence. Steady-state kinetics indicate that hPol κ contributes to greater G → T transversions by decreasing the specificity constant for dCTP compared to an isolated Fapy•dG. The greater conformational freedom of Fapy•dG compared to 8-OxodGuo and its unusual ability to epimerize at the anomeric center is believed to be the source of the complex effects of 5’-Fapy•dG-5fdU on replication. •G → T transversions increase >10-fold upon replication of 5’-8-OxodGuo-5fdU tandem lesion relative to 8-OxodGuo.•Mutation frequency of tandem 5’-Fapy•dG-5fdU is 3-fold greater in compared to isolated Fapy•dG.•5’-Fapy•dG-5fdU gave a more complex mutational pattern than 5’−8-OxodGuo-5fdU tandem lesion.•5fdU is much more mutagenic when it is part of a 5’-Fapy•dG-5fdU tandem lesion.