Misoprostol is listed in the WHO essential medicines list and can be used for induction of labour, for prevention and treatment of post-partum haemorrhage, and for abortions. The compound is unstable, and substandard misoprostol preparations have been detected in low- and middle-income countries. We now investigated the stability of misoprostol tablets according to the international guidelines for stability testing of pharmaceutical products. Three brands (four batches) of misoprostol tablets were collected in Malawi and Rwanda: the originator product, a WHO-prequalified product, and a generic product without WHO prequalification. A further batch of the originator product was collected in Germany. To investigate the effect of damage to the primary packaging, additional blister strips of one sample were intentionally damaged with a needle and investigated in parallel. Samples were placed in stability chambers for six months at 40°C/75% relative humidity (RH) and at 25°C/60% RH. After 0, 1, 2, 3 and 6 months, misoprostol content was determined according to the International Pharmacopeia. At 40°C/75% RH, all samples showed a decline of misoprostol content, but four of the batches still remained within the pharmacopeial specifications, while one of the two batches of the generic product without WHO-prequalification showed a final content of 86.2% which is out of specifications. Damage to the primary packaging greatly decreased stability, resulting in a final content of only 48.2% of the declared misoprostol amount. At 25°C/60% RH all samples remained in specifications for six months, even the sample with the damaged blister. Dissolution of misoprostol remained in specifications of the pharmacopoeia for six months for all batches, except for the sample with damaged blisters stored at 40°C/75% RH. This study confirms that the stability of misoprostol tablets must be ensured by intact, good-quality primary packaging. Careful supplier qualification is required in the procurement process.