Mechanical barriers prevent the invasion of the surrounding soft tissues within the bone defects. This concept is known as Guided Bone Regeneration (GBR). The knowledge about the local tissue reaction and the time of degradation of absorbable membranes favors the correct clinical indication. This study aimed to evaluate the biocompatibility and biodegradation of a bovine collagen membrane (Lyostypt®, São Gonçalo, Brazil) and compare it to a porcine collagen membrane (Bio-Gide®) implanted in the subcutaneous tissue of mice, following ISO 10993-6:2016. Thirty Balb-C mice were randomly divided into three experimental groups, LT (Lyostypt®), BG (Bio-Gide®), and Sham (without implantation), and subdivided according to the experimental periods (7, 21, and 63 days). The BG was considered non-irritant at seven days and slight and moderate irritant at 21 and 63 days, respectively. The LT presented a small irritant reaction at seven days, a mild reaction after 21, and a reduction in the inflammatory response at 63 days. The biodegradation of the LT occurred more rapidly compared to the BG after 63 days. This study concluded that both membranes were considered biocompatible since their tissue reactions were compatible with the physiological inflammatory process; however, the Bio-Gide® was less degraded during the experimental periods, favoring the guided bone regeneration process.