We examine the empirical link between collaborative R&D strategies and the research and innovation performance of small- and medium-sized enterprises in peripheral locations. Using a survey of German firms combined with time series information on patent applications obtained from the European Patent Office, we apply a comparison-group approach and estimate different “treatment effect” models to assess the notion of causality underlying this relationship. Besides accounting for observed and unobserved firm-specific heterogeneity, we thereby also control for the likely endogeneity of R&D collaboration as a strategic choice in the course of research and innovation activities. Our results for the period 2001–2007 indicate that engaging in R&D collaboration vis-á-vis a non-collaborative research strategy is related to higher outcome levels for a firm’s key research and innovation indicators such as R&D and patent intensity. We also find that this latter link varies by firm size and the organizational type of cooperating partner, and especially those firms that simultaneously engage in research collaborations with other private businesses and research institutes/universities show above average innovation performance. In contrast, the notion of spatial proximity to research partners is shown to be of less importance. Our results may be of help for the future design of regional policies supporting the research and innovation activity of small firms in peripheral and remote locations outside large metropolitan areas.