To compare the roles of programmed death 1 ligand 1 (PD‐L1) and PD‐L2 in regulating immunity to infection, we investigated responses of mice lacking PD‐L1 or PD‐L2 to infection with Leishmania mexicana. PD‐L1^–/– and PD‐L2^–/– mice exhibited distinct disease outcomes following infection with L. mexicana. In comparison to susceptible WT mice, PD‐L1^–/– mice showed resistance to L. mexicana, as demonstrated by reduced growth of cutaneous lesions and parasite burden. In contrast, PD‐L2^–/– mice developed exacerbated disease with increased parasite burden. Host resistance to L. mexicana is partly associated with the development of a Th1 response and down‐regulation of the Th2 response. Both PD‐L1^–/– and PD‐L2^–/– mice produced levels of IFN‐γ similar to WT mice. However, the development of IL‐4‐producing cells was reduced in PD‐L1^–/– mice, demonstrating a role for PD‐L1 in regulating Th cell differentiation. This inadequate Th2 response may explain the increased resistance of PD‐L1^–/– mice. Although no alterations in Th1/Th2 skewing were observed in PD‐L2^–/– mice, PD‐L2^–/– mice exhibited a marked increase in L. mexicana‐specific antibody production. Increased Leishmania‐specific IgG production may suppress the healing response through FcγR ligation on macrophages. Taken together, our results demonstrate that PD‐L1 and PD‐L2 have distinct roles in regulating the immune response to L. mexicana.