The combination of MEK inhibitor (cobimetinib, trametinib) and BRAF inhibitor (vemurafenib, dabrafenib) is now the first-line treatment in patients with BRAF V600-mutated metastatic melanoma. This association reduces cutaneous adverse events induced by BRAF inhibitors alone, including photosensitivity, hand-foot syndrome, hyperkeratosis, alopecia, skin papillomas, keratoacanthomas, and squamous-cell carcinomas. While panniculitis has exceptionally been reported with BRAF inhibitors, this rare side effect has never been described with the use of MEK inhibitors. We present here the first observation of panniculitis strictly induced by MEK inhibitors. Indeed, 10 days after the initiation of combined treatment with cobimetinib and vemurafenib for metastatic melanoma, our patient developed panniculitis predominantly on the upper and lower extremities. These cutaneous nodules disappeared during cobimetinib intermissions and recurred while the molecule was resumed. Recurrence of cutaneous nodules was observed after initiation of trametinib combined with dabrafenib, and resolved once again with trametinib discontinuation. We believe that clinicians should be aware of this cutaneous adverse event in patients treated with combined therapy, which can lead to unfounded BRAF inhibitor treatment discontinuation and compromise the antitumor response. Our case suggests a class effect linked with the MEK inhibition pharmacodynamic activity. Finally, laboratory investigation and histopathological examination are mandatory to exclude other panniculitis etiologies and subcutaneous metastasis of melanoma.