Introduction: Past research supports the efficacy of evidence-based literacy interventions for English-speaking struggling readers, but it remains unknown if similar results can be achieved in Spanish. Methods: We assessed the impact of a 15-hour long evidence-based literacy intervention for Spanish speaking struggling readers attending grade 1 and 2 in primary schools of vulnerable socio-economic status (SES) in Uruguay. Struggling readers were randomly assigned to a supplementary intervention (n = 68) in addition to business-as-usual classroom instruction or control group (n = 57) and compared to an additional group of typically developing readers (n = 69) on pre-post measures of phonological awareness, spelling, reading fluency and comprehension. Results: Although all participants showed significant improvements with respect to pre-posttest trajectories, struggling readers in the intervention group only achieved higher growth levels as compared to the control group on rhyme identification and partially for comprehension skills. Discussion and conclusions: Findings from this study underline the need to consider contrasts between the writing systems of Spanish and English, as well as cognitive profiles of children from vulnerable SES in Latin-America when applying evidence-based practices to design intervention programs for struggling readers from low SES in Spanish speaking countries.