In my opinion, the best neighborhood to stay in Medellin is in the Parque Lleras section of El Poblado. This is a safe, affluent area with great boutique hotels, stores and many restaurants. I recommend staying in one of two properties:
Art Hotel Medellin: This is the hotel I chose at Carrera 41 #9-31 Poblado. It has a unique, contemporary, minimalist design with open courtyard and many exposed brick walls. My room was well appointed and comfortable. I think, overall, it needs a little freshening, but the dining room was nice, the location was excellent and the staff very helpful. They helped me find an excellent guide for my touring of Medellin that had been featured in a recent article by the New York Times.
The Charlee Lifestyle Hotel: At Calle 9a#31-16, I checked out this upscale, boutique hotel that has a great exterior as well as interior design. I also liked the location across from Parque Lleras. I would definitely try this hotel on my next trip.