We examined the extent to which self-efficacy and growth mindsets predict reading comprehension growth in sixth grade and the moderating role of initial word reading. Students (N = 303) reported on their self-efficacy as well as domain-general and reading-specific mindsets at the beginning of sixth grade. They completed brief bi-monthly reading comprehension measures throughout the year and a multiple-choice reading comprehension measure at the end of the school year. Results from a series of latent basis growth models indicated that self-efficacy predicted the initial level but not growth in reading comprehension. In contrast, a domain-general growth mindset did not predict the initial level but did predict growth, which in turn predicted the end-of-year reading comprehension outcome. Unexpectedly, a reading-specific growth mindset predicted none of the reading comprehension outcomes, and the initial word reading skill did not moderate the relation between growth mindsets and reading comprehension growth. Our findings highlight the critical role that self-efficacy and a domain-general growth mindset play in promoting students' reading comprehension development.