Perinatal mortality of lambs is the major source of reproductive loss in extensive sheep production systems. Treatment with caffeine has reduced intra-partum mortality and/or improved metabolic indicators in other species following hypoxia. This study was conducted to evaluate the efficacy of caffeine for improving perinatal lamb survival. Experiment 1 comprised group-fed Merino ewes grazing pasture and offered 1.8 g/day (estimated 20 mg/kg live weight) caffeine throughout a 4-week lambing period, and a control without caffeine. The survival of lambs to marking (vaccinated, tail docked, males castrated) age in the caffeine treatment group (0.81) did not differ (P = 0.199) from that of control lambs (0.73; total born n = 877). Experiment 2 comprised Merino ewes lambing from three successive weekly joining groups. Treated ewes were drenched with an aqueous caffeine solution at a dose rate of 10 mg/kg live weight from the day before anticipated lambing, until the individual lambed. Control ewes were drenched with water. The proportion of lambs born dead (0.07) and the survival of lambs to marking age (caffeine 0.61; control 0.62) were similar between treatment groups (total born n = 1158). In both experiments, ewe mortality and the weight of lambs at marking were not altered by caffeine treatments. The results from this large-scale field study indicate caffeine is not an effective therapeutic agent to increase either intra-partum or perinatal survival, or lamb growth rates.